NZ623879B2 - Treatment of rhinitis - Google Patents
Treatment of rhinitis Download PDFInfo
- Publication number
- NZ623879B2 NZ623879B2 NZ623879A NZ62387912A NZ623879B2 NZ 623879 B2 NZ623879 B2 NZ 623879B2 NZ 623879 A NZ623879 A NZ 623879A NZ 62387912 A NZ62387912 A NZ 62387912A NZ 623879 B2 NZ623879 B2 NZ 623879B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- dkp
- composition
- kda
- less
- pharmaceutical product
- Prior art date
Links
- 206010039083 Rhinitis Diseases 0.000 title claims abstract description 51
- 239000000203 mixture Substances 0.000 claims abstract description 112
- 108010038239 aspartyl-alanyl-diketopiperazine Proteins 0.000 claims abstract description 77
- 239000000825 pharmaceutical preparation Substances 0.000 claims abstract description 31
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 16
- BXRNXXXXHLBUKK-UHFFFAOYSA-N piperazine-2,5-dione Chemical compound O=C1CNC(=O)CN1 BXRNXXXXHLBUKK-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229960005261 Aspartic Acid Drugs 0.000 claims abstract description 5
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims abstract description 5
- 150000001413 amino acids Chemical group 0.000 claims abstract description 5
- 235000003704 aspartic acid Nutrition 0.000 claims abstract description 5
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims abstract description 4
- 235000004279 alanine Nutrition 0.000 claims abstract description 4
- 239000003814 drug Substances 0.000 claims description 32
- 229940079593 drugs Drugs 0.000 claims description 25
- 239000007921 spray Substances 0.000 claims description 18
- -1 paraffins Substances 0.000 claims description 17
- 210000001331 Nose Anatomy 0.000 claims description 15
- 239000011780 sodium chloride Substances 0.000 claims description 15
- 238000000108 ultra-filtration Methods 0.000 claims description 15
- 102100001249 ALB Human genes 0.000 claims description 14
- 101710027066 ALB Proteins 0.000 claims description 14
- 102000008100 Human Serum Albumin Human genes 0.000 claims description 14
- 108091006822 Human Serum Albumin Proteins 0.000 claims description 14
- 206010039085 Rhinitis allergic Diseases 0.000 claims description 14
- 229940050528 albumin Drugs 0.000 claims description 14
- 201000010105 allergic rhinitis Diseases 0.000 claims description 14
- 239000012528 membrane Substances 0.000 claims description 12
- 239000000706 filtrate Substances 0.000 claims description 11
- 206010028735 Nasal congestion Diseases 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 9
- 206010039101 Rhinorrhoea Diseases 0.000 claims description 8
- 238000010521 absorption reaction Methods 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- 229920001223 polyethylene glycol Polymers 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- XLOMVQKBTHCTTD-UHFFFAOYSA-N zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 claims description 8
- 206010041232 Sneezing Diseases 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 7
- 239000003921 oil Substances 0.000 claims description 7
- RMAQACBXLXPBSY-UHFFFAOYSA-N Silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 claims description 6
- 229920002472 Starch Polymers 0.000 claims description 6
- 235000012216 bentonite Nutrition 0.000 claims description 6
- 235000019198 oils Nutrition 0.000 claims description 6
- 239000003380 propellant Substances 0.000 claims description 6
- 238000000926 separation method Methods 0.000 claims description 6
- 235000012239 silicon dioxide Nutrition 0.000 claims description 6
- 235000019698 starch Nutrition 0.000 claims description 6
- 239000000375 suspending agent Substances 0.000 claims description 6
- 239000000454 talc Substances 0.000 claims description 6
- 235000012222 talc Nutrition 0.000 claims description 6
- 229910052623 talc Inorganic materials 0.000 claims description 6
- 241000416162 Astragalus gummifer Species 0.000 claims description 5
- 206010052437 Nasal discomfort Diseases 0.000 claims description 5
- 229940116362 Tragacanth Drugs 0.000 claims description 5
- 229920001615 Tragacanth Polymers 0.000 claims description 5
- 239000000739 antihistaminic agent Substances 0.000 claims description 5
- 238000004587 chromatography analysis Methods 0.000 claims description 5
- 239000002270 dispersing agent Substances 0.000 claims description 5
- 239000008107 starch Substances 0.000 claims description 5
- 235000010487 tragacanth Nutrition 0.000 claims description 5
- 239000000196 tragacanth Substances 0.000 claims description 5
- 239000001993 wax Substances 0.000 claims description 5
- 210000000138 Mast Cells Anatomy 0.000 claims description 4
- 230000001387 anti-histamine Effects 0.000 claims description 4
- 239000001913 cellulose Substances 0.000 claims description 4
- 235000010980 cellulose Nutrition 0.000 claims description 4
- 229920002678 cellulose Polymers 0.000 claims description 4
- 239000000850 decongestant Substances 0.000 claims description 4
- 229920001296 polysiloxane Polymers 0.000 claims description 4
- 238000001556 precipitation Methods 0.000 claims description 4
- 238000000527 sonication Methods 0.000 claims description 4
- 239000003381 stabilizer Substances 0.000 claims description 4
- 238000000856 sucrose gradient centrifugation Methods 0.000 claims description 4
- 235000019871 vegetable fat Nutrition 0.000 claims description 4
- 239000011787 zinc oxide Substances 0.000 claims description 4
- 235000014692 zinc oxide Nutrition 0.000 claims description 4
- DDMOUSALMHHKOS-UHFFFAOYSA-N 1,2-dichloro-1,1,2,2-tetrafluoroethane Chemical compound FC(F)(Cl)C(F)(F)Cl DDMOUSALMHHKOS-UHFFFAOYSA-N 0.000 claims description 3
- 229960004424 Carbon Dioxide Drugs 0.000 claims description 3
- PXBRQCKWGAHEHS-UHFFFAOYSA-N Dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 3
- 239000004338 Dichlorodifluoromethane Substances 0.000 claims description 3
- 229940087091 Dichlorotetrafluoroethane Drugs 0.000 claims description 3
- 239000002202 Polyethylene glycol Substances 0.000 claims description 3
- CYRMSUTZVYGINF-UHFFFAOYSA-N Trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 claims description 3
- 230000003110 anti-inflammatory Effects 0.000 claims description 3
- 239000002260 anti-inflammatory agent Substances 0.000 claims description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims description 3
- 239000001569 carbon dioxide Substances 0.000 claims description 3
- 229910002092 carbon dioxide Inorganic materials 0.000 claims description 3
- 238000003745 diagnosis Methods 0.000 claims description 3
- 229940042935 dichlorodifluoromethane Drugs 0.000 claims description 3
- 235000019404 dichlorodifluoromethane Nutrition 0.000 claims description 3
- 239000003623 enhancer Substances 0.000 claims description 3
- 230000002708 enhancing Effects 0.000 claims description 3
- 150000002617 leukotrienes Chemical class 0.000 claims description 3
- 239000003607 modifier Substances 0.000 claims description 3
- 239000002562 thickening agent Substances 0.000 claims description 3
- 229940029284 trichlorofluoromethane Drugs 0.000 claims description 3
- 239000003925 fat Substances 0.000 claims description 2
- 235000019197 fats Nutrition 0.000 claims description 2
- 239000003961 penetration enhancing agent Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 230000035492 administration Effects 0.000 description 35
- 150000001875 compounds Chemical class 0.000 description 20
- 239000000843 powder Substances 0.000 description 16
- 108010016626 Dipeptides Proteins 0.000 description 15
- 239000004480 active ingredient Substances 0.000 description 13
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 229940068196 placebo Drugs 0.000 description 11
- 239000000902 placebo Substances 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000002585 base Substances 0.000 description 8
- 235000019441 ethanol Nutrition 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- 230000002194 synthesizing Effects 0.000 description 8
- 230000002009 allergen Effects 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 230000002354 daily Effects 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 108010010803 Gelatin Proteins 0.000 description 6
- WVDDGKGOMKODPV-UHFFFAOYSA-N benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- 239000002552 dosage form Substances 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 239000000499 gel Substances 0.000 description 6
- 239000008273 gelatin Substances 0.000 description 6
- 229920000159 gelatin Polymers 0.000 description 6
- 235000019322 gelatine Nutrition 0.000 description 6
- 235000011852 gelatine desserts Nutrition 0.000 description 6
- 230000002458 infectious Effects 0.000 description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N n-butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- 239000000969 carrier Substances 0.000 description 5
- 239000006071 cream Substances 0.000 description 5
- 235000011187 glycerol Nutrition 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 239000002674 ointment Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 229960004784 ALLERGENS Drugs 0.000 description 4
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 description 4
- 229940032147 Starch Drugs 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 4
- 102000004965 antibodies Human genes 0.000 description 4
- 108090001123 antibodies Proteins 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- GUBGYTABKSRVRQ-XLOQQCSPSA-N 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 4
- 239000008101 lactose Substances 0.000 description 4
- 239000006187 pill Substances 0.000 description 4
- 229920000642 polymer Polymers 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 4
- 238000007363 ring formation reaction Methods 0.000 description 4
- CZMRCDWAGMRECN-UGDNZRGBSA-N D-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 3
- 229940071648 Metered Dose Inhaler Drugs 0.000 description 3
- CZMRCDWAGMRECN-GDQSFJPYSA-N Sucrose Natural products O([C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1)[C@@]1(CO)[C@H](O)[C@@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-GDQSFJPYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M buffer Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 239000000428 dust Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000003995 emulsifying agent Substances 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000003701 inert diluent Substances 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000011347 resin Substances 0.000 description 3
- 229920005989 resin Polymers 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 230000000699 topical Effects 0.000 description 3
- 239000000080 wetting agent Substances 0.000 description 3
- BTANRVKWQNVYAZ-UHFFFAOYSA-N 2-Butanol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 2
- VUKAUDKDFVSVFT-UHFFFAOYSA-N 2-[6-[4,5-bis(2-hydroxypropoxy)-2-(2-hydroxypropoxymethyl)-6-methoxyoxan-3-yl]oxy-4,5-dimethoxy-2-(methoxymethyl)oxan-3-yl]oxy-6-(hydroxymethyl)-5-methoxyoxane-3,4-diol Chemical compound COC1C(OC)C(OC2C(C(O)C(OC)C(CO)O2)O)C(COC)OC1OC1C(COCC(C)O)OC(OC)C(OCC(C)O)C1OCC(C)O VUKAUDKDFVSVFT-UHFFFAOYSA-N 0.000 description 2
- 229920001817 Agar Polymers 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
- VZGDMQKNWNREIO-UHFFFAOYSA-N Carbon tetrachloride Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 241000206672 Gelidium Species 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 241000282414 Homo sapiens Species 0.000 description 2
- 206010020751 Hypersensitivity Diseases 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 150000008575 L-amino acids Chemical class 0.000 description 2
- 240000007472 Leucaena leucocephala Species 0.000 description 2
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 2
- 210000004379 Membranes Anatomy 0.000 description 2
- 229940100662 Nasal Drops Drugs 0.000 description 2
- 229940097496 Nasal Spray Drugs 0.000 description 2
- 229960004063 Propylene glycol Drugs 0.000 description 2
- 210000003491 Skin Anatomy 0.000 description 2
- JNYAEWCLZODPBN-CTQIIAAMSA-N Sorbitan Chemical compound OCC(O)C1OCC(O)[C@@H]1O JNYAEWCLZODPBN-CTQIIAAMSA-N 0.000 description 2
- 238000000692 Student's t-test Methods 0.000 description 2
- HWKQNAWCHQMZHK-UHFFFAOYSA-N Trolnitrate Chemical compound [O-][N+](=O)OCCN(CCO[N+]([O-])=O)CCO[N+]([O-])=O HWKQNAWCHQMZHK-UHFFFAOYSA-N 0.000 description 2
- 208000001319 Vasomotor Rhinitis Diseases 0.000 description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 238000007792 addition Methods 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 230000000240 adjuvant Effects 0.000 description 2
- 239000000443 aerosol 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
- 201000005794 allergic hypersensitivity disease Diseases 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminum Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000002567 autonomic Effects 0.000 description 2
- 239000000440 bentonite Substances 0.000 description 2
- 229910000278 bentonite Inorganic materials 0.000 description 2
- 235000019445 benzyl alcohol Nutrition 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 229920002988 biodegradable polymer Polymers 0.000 description 2
- 239000004621 biodegradable polymer Substances 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 239000006184 cosolvent Substances 0.000 description 2
- 230000003111 delayed Effects 0.000 description 2
- 239000008298 dragée Substances 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 230000004907 flux Effects 0.000 description 2
- 230000001339 gustatory Effects 0.000 description 2
- 230000003054 hormonal Effects 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- 230000028993 immune response Effects 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 230000004301 light adaptation Effects 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 239000008297 liquid dosage form Substances 0.000 description 2
- 239000000314 lubricant 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
- 239000011159 matrix material Substances 0.000 description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 2
- 239000004530 micro-emulsion Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000006011 modification reaction Methods 0.000 description 2
- 238000000465 moulding Methods 0.000 description 2
- 239000007922 nasal spray Substances 0.000 description 2
- 239000006199 nebulizer Substances 0.000 description 2
- 230000001264 neutralization Effects 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N o-xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- 239000004006 olive oil Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000006072 paste Substances 0.000 description 2
- 239000003186 pharmaceutical solution Substances 0.000 description 2
- 238000001050 pharmacotherapy Methods 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 229920003023 plastic Polymers 0.000 description 2
- 239000004033 plastic Substances 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000000770 pro-inflamatory Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 235000018102 proteins Nutrition 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000007909 solid dosage form Substances 0.000 description 2
- 239000007790 solid phase Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 150000008163 sugars Chemical class 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N t-BuOH Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 2
- 230000001960 triggered Effects 0.000 description 2
- 230000001457 vasomotor Effects 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- PNBMXFUTFSFLNU-BXRBKJIMSA-N (2S)-2-aminobutanedioic acid;(2S)-2-aminopropanoic acid Chemical compound C[C@H](N)C(O)=O.OC(=O)[C@@H](N)CC(O)=O PNBMXFUTFSFLNU-BXRBKJIMSA-N 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N 1,1-Diethoxyethane Chemical compound CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N 1,2-ethanediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 229940058015 1,3-butylene glycol Drugs 0.000 description 1
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 description 1
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 description 1
- JNODDICFTDYODH-UHFFFAOYSA-N 2-hydroxytetrahydrofuran Chemical compound OC1CCCO1 JNODDICFTDYODH-UHFFFAOYSA-N 0.000 description 1
- AQIXEPGDORPWBJ-UHFFFAOYSA-N 3-Pentanol Chemical compound CCC(O)CC AQIXEPGDORPWBJ-UHFFFAOYSA-N 0.000 description 1
- YJISHJVIRFPGGN-UHFFFAOYSA-N 5-[5-[3,4-dihydroxy-6-(hydroxymethyl)-5-methoxyoxan-2-yl]oxy-6-[[3,4-dihydroxy-6-(hydroxymethyl)-5-methoxyoxan-2-yl]oxymethyl]-3,4-dihydroxyoxan-2-yl]oxy-6-(hydroxymethyl)-2-methyloxane-3,4-diol Chemical compound O1C(CO)C(OC)C(O)C(O)C1OCC1C(OC2C(C(O)C(OC)C(CO)O2)O)C(O)C(O)C(OC2C(OC(C)C(O)C2O)CO)O1 YJISHJVIRFPGGN-UHFFFAOYSA-N 0.000 description 1
- XJKJWTWGDGIQRH-BFIDDRIFSA-N Alginic acid Chemical compound O1[C@@H](C(O)=O)[C@@H](OC)[C@H](O)[C@H](O)[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](C)[C@@H](O)[C@H]1O XJKJWTWGDGIQRH-BFIDDRIFSA-N 0.000 description 1
- XXROGKLTLUQVRX-UHFFFAOYSA-N Allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K Aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- PZZYQPZGQPZBDN-UHFFFAOYSA-N Aluminium silicate Chemical compound O=[Al]O[Si](=O)O[Al]=O PZZYQPZGQPZBDN-UHFFFAOYSA-N 0.000 description 1
- 229940006211 Anticholinergic mydriatics and cycloplegics Drugs 0.000 description 1
- 229940065524 Anticholinergics inhalants for obstructive airway diseases Drugs 0.000 description 1
- 235000003276 Apios tuberosa Nutrition 0.000 description 1
- 240000005781 Arachis hypogaea Species 0.000 description 1
- 235000010777 Arachis hypogaea Nutrition 0.000 description 1
- 235000010744 Arachis villosulicarpa Nutrition 0.000 description 1
- 208000006673 Asthma Diseases 0.000 description 1
- MBUVEWMHONZEQD-UHFFFAOYSA-N Azeptin Chemical compound C1CN(C)CCCC1N1C(=O)C2=CC=CC=C2C(CC=2C=CC(Cl)=CC=2)=N1 MBUVEWMHONZEQD-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 206010060945 Bacterial infection Diseases 0.000 description 1
- 229940092705 Beclomethasone Drugs 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 210000004369 Blood Anatomy 0.000 description 1
- 210000004204 Blood Vessels Anatomy 0.000 description 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- 229960003563 Calcium Carbonate Drugs 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
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate dianion Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N Cetyl alcohol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
- 229940009997 Cromolyn Drugs 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 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
- WQZGKKKJIJFFOK-GASJEMHNSA-N D-Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- FBPFZTCFMRRESA-KAZBKCHUSA-N D-Mannitol Natural products OC[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KAZBKCHUSA-N 0.000 description 1
- 150000008574 D-amino acids Chemical class 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
- NEFBYIFKOOEVPA-UHFFFAOYSA-K Dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N Diphenhydramine Chemical compound C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 1
- 229960005178 Doxylamine Drugs 0.000 description 1
- HCFDWZZGGLSKEP-UHFFFAOYSA-N Doxylamine Chemical compound C=1C=CC=NC=1C(C)(OCCN(C)C)C1=CC=CC=C1 HCFDWZZGGLSKEP-UHFFFAOYSA-N 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N Ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- RWTNPBWLLIMQHL-UHFFFAOYSA-N Fexofenadine Chemical compound C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- XSFJVAJPIHIPKU-XWCQMRHXSA-N Flunisolide Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[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 XSFJVAJPIHIPKU-XWCQMRHXSA-N 0.000 description 1
- WMWTYOKRWGGJOA-CENSZEJFSA-N Fluticasone propionate Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)SCF)(OC(=O)CC)[C@@]2(C)C[C@@H]1O WMWTYOKRWGGJOA-CENSZEJFSA-N 0.000 description 1
- 210000001035 Gastrointestinal Tract Anatomy 0.000 description 1
- 229960002989 Glutamic Acid Drugs 0.000 description 1
- 229940093915 Gynecological Organic acids Drugs 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 239000004705 High-molecular-weight polyethylene Substances 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
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 229940067606 Lecithin Drugs 0.000 description 1
- 229960003088 Loratadine Drugs 0.000 description 1
- JCCNYMKQOSZNPW-UHFFFAOYSA-N Loratadine Chemical compound C1CN(C(=O)OCC)CCC1=C1C2=NC=CC=C2CCC2=CC(Cl)=CC=C21 JCCNYMKQOSZNPW-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- VHRSUDSXCMQTMA-PJHHCJLFSA-N 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
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 210000004080 Milk Anatomy 0.000 description 1
- 229960001664 Mometasone Drugs 0.000 description 1
- 210000004400 Mucous Membrane Anatomy 0.000 description 1
- ACTNHJDHMQSOGL-UHFFFAOYSA-N N',N'-dibenzylethane-1,2-diamine Chemical compound C=1C=CC=CC=1CN(CCN)CC1=CC=CC=C1 ACTNHJDHMQSOGL-UHFFFAOYSA-N 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
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 235000003177 Panax trifolius Nutrition 0.000 description 1
- 229960001802 Phenylephrine Drugs 0.000 description 1
- SONNWYBIRXJNDC-VIFPVBQESA-N Phenylephrine Chemical compound CNC[C@H](O)C1=CC=CC(O)=C1 SONNWYBIRXJNDC-VIFPVBQESA-N 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000004952 Polyamide Substances 0.000 description 1
- 229920002732 Polyanhydride Polymers 0.000 description 1
- 229920000954 Polyglycolide Polymers 0.000 description 1
- 229920001710 Polyorthoester Polymers 0.000 description 1
- OIGNJSKKLXVSLS-VWUMJDOOSA-N Prednisolone Chemical compound O=C1C=C[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 OIGNJSKKLXVSLS-VWUMJDOOSA-N 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
- 208000003251 Pruritus Diseases 0.000 description 1
- KWGRBVOPPLSCSI-WCBMZHEXSA-N Pseudoephedrine Chemical compound CN[C@@H](C)[C@@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WCBMZHEXSA-N 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-N Salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 1
- 210000000162 Simple eye Anatomy 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 240000001016 Solanum tuberosum Species 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
- CBEQULMOCCWAQT-WOJGMQOQSA-N Triprolidine Chemical compound C1=CC(C)=CC=C1C(\C=1N=CC=CC=1)=C/CN1CCCC1 CBEQULMOCCWAQT-WOJGMQOQSA-N 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K Trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- 206010070488 Upper-airway cough syndrome Diseases 0.000 description 1
- 206010047461 Viral infection Diseases 0.000 description 1
- 208000001756 Virus Disease Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Vitamin C Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- 240000008042 Zea mays Species 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
- 239000003655 absorption accelerator Substances 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 230000001154 acute Effects 0.000 description 1
- 230000001058 adult Effects 0.000 description 1
- 238000001042 affinity chromatography Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 238000005349 anion exchange Methods 0.000 description 1
- 230000001078 anti-cholinergic Effects 0.000 description 1
- 230000000111 anti-oxidant Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 229940027983 antiseptics and disinfectants Quaternary ammonium compounds Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 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
- 229960004574 azelastine Drugs 0.000 description 1
- 238000003287 bathing Methods 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- NBMKJKDGKREAPL-DVTGEIKXSA-N beclomethasone 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)CO)(O)[C@@]1(C)C[C@@H]2O NBMKJKDGKREAPL-DVTGEIKXSA-N 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 229960004217 benzyl alcohol Drugs 0.000 description 1
- 229960002903 benzyl benzoate Drugs 0.000 description 1
- 235000013361 beverage Nutrition 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- IJDNQMDRQITEOD-UHFFFAOYSA-N butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 1
- 239000001273 butane Substances 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- PUPZLCDOIYMWBV-UHFFFAOYSA-N butylene glycol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 235000012241 calcium silicate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 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
- 239000004359 castor oil Substances 0.000 description 1
- 238000005341 cation exchange Methods 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 229960001803 cetirizine Drugs 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- QELSEDARGPSSRG-UHFFFAOYSA-N chlorobenzene;chloroform Chemical compound ClC(Cl)Cl.ClC1=CC=CC=C1 QELSEDARGPSSRG-UHFFFAOYSA-N 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 230000001684 chronic Effects 0.000 description 1
- 239000004927 clay Substances 0.000 description 1
- 229910052570 clay Inorganic materials 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 201000009230 common cold Diseases 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 235000005824 corn Nutrition 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 229960000265 cromoglicic acid Drugs 0.000 description 1
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 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
- 239000003085 diluting agent Substances 0.000 description 1
- 229960000520 diphenhydramine Drugs 0.000 description 1
- 239000007884 disintegrant Substances 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
- 238000004090 dissolution Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 229940093499 ethyl acetate Drugs 0.000 description 1
- CQDGTJPVBWZJAZ-UHFFFAOYSA-M ethyl carbonate Chemical compound CCOC([O-])=O CQDGTJPVBWZJAZ-UHFFFAOYSA-M 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229960003592 fexofenadine Drugs 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 229960000676 flunisolide Drugs 0.000 description 1
- 229960000289 fluticasone propionate Drugs 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000003517 fume Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 229940046528 grass pollen Drugs 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 235000011167 hydrochloric acid Nutrition 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxyl anion Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 230000001771 impaired Effects 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 230000000266 injurious Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 230000003522 irritant Effects 0.000 description 1
- 239000002085 irritant Substances 0.000 description 1
- 231100000021 irritant Toxicity 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- ZKLPARSLTMPFCP-UHFFFAOYSA-N levocetirizine Chemical compound C1CN(CCOCC(=O)O)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZKLPARSLTMPFCP-UHFFFAOYSA-N 0.000 description 1
- 230000000670 limiting Effects 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- HPQVWDOOUQVBTO-UHFFFAOYSA-N lithium aluminium hydride Substances [Li+].[Al-] HPQVWDOOUQVBTO-UHFFFAOYSA-N 0.000 description 1
- OCZDCIYGECBNKL-UHFFFAOYSA-N lithium;alumanuide Chemical compound [Li+].[AlH4-] OCZDCIYGECBNKL-UHFFFAOYSA-N 0.000 description 1
- 239000006210 lotion Substances 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
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 229940043265 methyl isobutyl ketone Drugs 0.000 description 1
- 229960004584 methylprednisolone Drugs 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
- 239000004005 microsphere Substances 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000007932 molded tablet Substances 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
- IMNFDUFMRHMDMM-UHFFFAOYSA-N n-heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 1
- 229960002009 naproxen Drugs 0.000 description 1
- 201000009240 nasopharyngitis Diseases 0.000 description 1
- 230000003472 neutralizing Effects 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 230000003000 nontoxic Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000002892 organic cations Chemical class 0.000 description 1
- 150000002895 organic esters Chemical class 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 235000010603 pastilles Nutrition 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 230000002085 persistent Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 239000011528 polyamide (building material) Substances 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 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
- 229960005205 prednisolone Drugs 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- 230000002335 preservative Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 230000002035 prolonged Effects 0.000 description 1
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 229950010450 pseudophedrine Drugs 0.000 description 1
- 230000036632 reaction speed Effects 0.000 description 1
- 230000002829 reduced Effects 0.000 description 1
- 239000003638 reducing agent Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 239000003340 retarding agent Substances 0.000 description 1
- 230000001932 seasonal Effects 0.000 description 1
- 230000035945 sensitivity 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
- 201000009890 sinusitis Diseases 0.000 description 1
- 238000001542 size-exclusion chromatography Methods 0.000 description 1
- 230000035943 smell Effects 0.000 description 1
- 239000000779 smoke Substances 0.000 description 1
- 239000001187 sodium carbonate Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000002522 swelling Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000001225 therapeutic Effects 0.000 description 1
- 210000001519 tissues Anatomy 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 229940046536 tree pollen allergenic extracts Drugs 0.000 description 1
- 229960005294 triamcinolone Drugs 0.000 description 1
- 229960001128 triprolidine Drugs 0.000 description 1
- 239000011778 trisodium citrate Substances 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N β-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
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/38—Albumins
- A61K38/385—Serum albumin
-
- 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
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0043—Nose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M11/00—Sprayers or atomisers specially adapted for therapeutic purposes
- A61M11/02—Sprayers or atomisers specially adapted for therapeutic purposes operated by air or other gas pressure applied to the liquid or other product to be sprayed or atomised
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M15/00—Inhalators
- A61M15/0065—Inhalators with dosage or measuring devices
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M15/00—Inhalators
- A61M15/009—Inhalators using medicine packages with incorporated spraying means, e.g. aerosol cans
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M15/00—Inhalators
- A61M15/08—Inhaling devices inserted into the nose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M2202/00—Special media to be introduced, removed or treated
- A61M2202/06—Solids
- A61M2202/064—Powder
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/02—Nasal agents, e.g. decongestants
-
- 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
Abstract
The disclosure provides a method of treating rhinitis. The method comprises administering an effective amount of a pharmaceutical composition comprising a diketopiperazine with amino acid side chains of aspartic acid and alanine (DA-DKP) formulated for nasal administration. The Disclosure also provides a pharmaceutical product comprising a DA-DKP containing composition. des a pharmaceutical product comprising a DA-DKP containing composition.
Description
TREATMENT OF RHINITIS
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of priority under 35 U.S.C. §119(e) to U.S. Provisional
Patent Application No. 61/552,508, filed October 28, 2011 and U.S. Provisional Patent
Application No. 61/561,215, filed November 17, 2011. The entire disclosures of each U.S.
Provisional Patent Applications Nos. 61/552,508 and 61/561,215 are incorporated herein by
reference.
FIELD OF INVENTION
The invention relates to a method of treating rhinitis. The method comprises
administering an effective amount of a pharmaceutical composition comprising a diketopiperazine
with amino acid side chains of aspartic acid and alanine (DA-DKP). The invention also provides
a pharmaceutical product comprising a DA-DKP containing composition.
BACKGROUND
Rhinitis is caused by chronic or acute inflammation of the mucous membranes of the nose
due to viruses, bacteria or irritants. The inflammation results in the generation of excessive
amounts of mucous, commonly producing a runny nose, nasal congestion and post-nasal drip.
Rhinitis is reported to affect more than 50 million people in the United States alone.
There are several types of rhinitis, including infectious rhinitis, allergic rhinitis and
nonallergic rhinitis. Infectious rhinitis is caused by a viral or bacterial infection. Types of
infectious rhinitis include the common cold and sinusitis.
Allergic rhinitis affects more than 20% of people worldwide and the prevalence increases
annually. Allergic rhinitis causes impaired social life, sleep, school, and work. The quality of life
of patients can be altered by the severity and duration of rhinitis. Allergic rhinitis is a
proinflammatory immune response to outdoor or indoor allergens, such as dust or pollen.
Symptoms can occur year-round or primarily be at certain times of the year, usually in the spring,
summer or fall. The Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines outlines the
management of allergic rhinitis as allergen avoidance, patient education, pharmacotherapy, and
allergen-specific immunotherapy. For pharmacotherapy, ARIA currently recommends intranasal,
second-generation H1-antihistamines and an intranasal corticosteroid for moderate to severe
persistent disease. See Bousquet et al., J. Allergy Clin. Immunol., 108(Suppl 5):S147-334 (2001)
and Bousquet et al., Allergy, 63(Suppl. 86):8-160 (2008).
Nonallergic rhinitis is rhinitis that is not triggered by allergens or infectious agents. There
is still much to be learned about nonallergic rhinitis, but it is thought that the triggers of it cause
dilation of the blood vessels in the lining of the nose, which results in swelling and drainage.
Types of nonallergic rhinitis include vasomotor, autonomic, hormonal, drug-induced, atrophic and
gustatory rhinitis and rhinitis medicamentosa. Triggers of vasomotor rhinitis include smells,
fumes, smoke, dust and temperature changes, and vasomotor rhinitis can coexist with allergic
rhinitis. Rhinitis medicamentosa is a condition of rebound nasal congestion brought on by
extended use of topical decongestants.
SUMMARY OF THE INVENTION
One embodiment of the invention relates to a method of treating rhinitis by administering
an effective amount of a pharmaceutical composition comprising a diketopiperazine with amino
acid side chains of aspartic acid and alanine (DA-DKP), to an animal in need thereof. In one
aspect, the rhinitis is allergic rhinitis.
In one aspect, the effective amount of the DA-DKP in the composition is from about 100
µg to about 3000 µg per day. In another aspect, the effective amount of the DA-DKP in the
composition is from about 500 µg to about 1500 µg per day.
In yet other aspects, the administration of the composition comprising DA-DKP, is
commenced within 24 hours of diagnosis of rhinitis. In still other aspects, the administration of
the composition comprising DA-DKP, is commenced at the appearance of one or more early signs
of, or a predisposition to develop, rhinitis. One or more early signs of rhinitis can be rhinorrhea,
nasal congestion, nasal itching and sneezing.
In yet other aspects of the method, the DA-DKP is in a composition prepared by removing
albumin from a solution of a human serum albumin composition. For example, the step of
removing can be by treating the human serum albumin composition by a separation method. Such
separation methods can include ultrafiltration, sucrose gradient centrifugation, chromatography,
salt precipitation, and sonication. In addition, the step of removing can be by passing the human
serum albumin composition over an ultrafiltration membrane with a molecular weight cut off that
retains the albumin, and the resulting filtrate contains the DA-DKP. In one aspect, the
ultrafiltration membrane has a molecular weight cutoff of less than 50 kDa. In still another
aspect, the ultrafiltration membrane has a molecular weight cut off less than 40 kDa, less than 30
kDa, less than 20 kDa, less than 10 kDa, less than 5 kDa or less than 3 kDa.
In yet another aspect, the composition comprising DA-DKP is administered in
combination with a second drug suitable for treating rhinitis. For example, the second drug can be
selected from antihistamines, decongestants, anti-inflammatories, mast cell stabilizers, leukotriene
modifiers and IgE blockers.
Another embodiment of the invention relates to a pharmaceutical product, comprising a
DA-DKP containing composition formulated for administration by a route selected from
inhalation, insufflation and nasal administration to the nose. In one aspect, the DA-DKP
containing composition formulated for administration by inhalation is packaged in a device
selected from insufflators, nebulizers, pressurized packs, squeeze bottle, a syringe, a dropper, a
spray device, an atomizer device, and an aerosolizer. In one aspect, the pressurized pack can
comprise a propellant selected from dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetrafluoroethane, and carbon dioxide.
In still another aspect of the pharmaceutical product, the DA-DKP containing composition
formulated for administration by inhalation or insufflation comprises a powder mix of the DA-
DKP containing composition and a powder base. In one aspect, the powder mix can be in a
dosage form selected from capsules, cartridges, gelatin packs and blister packs. The powder mix
can be delivered by a device selected from an inhalator, insufflator and metered-dose inhaler.
In yet another aspect of the pharmaceutical product, the DA-DKP containing composition
formulated for nasal administration is in a form of drops or sprays. In one aspect, the DA-DKP in
the DA-DKP containing composition comprises from about 0.1% (w/v) to about 10% (w/v) of the
composition. The drops or sprays can be contained within an intranasal delivery system. In one
aspect, the intranasal delivery system comprises an atomizing device. In one aspect, the
atomizing device comprises a bottle and pump. In a preferred aspect, the pump is a metered dose
pump. The metered dose pump can deliver an intranasal volume of the DA-DKP containing
composition. In one aspect, the metered dose pump can deliver an intranasal volume of about
0.15 ml of the DA-DKP containing composition per pump. In still another pharmaceutical
product further comprises an aqueous or non-aqueous base comprising one or more agents
selected from dispersing agents, solubilizing agents, and suspending agents.
In still another aspect of the pharmaceutical product, the DA-DKP containing composition
is formulated for nasal administration in a form selected from ointments, gels and creams. In one
aspect, pharmaceutical product further comprises excipients selected from animal fats, vegetable
fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicones,
bentonites, silicic acid, talc, zinc oxide and mixtures thereof. In still another aspect, the
pharmaceutical product further comprises an absorption or permeation enhancer. In yet another
aspect, the pharmaceutical product further comprises a thickening agent or viscosity enhancer to
increase the residence time of the DA-DKP containing composition in the nose. In still another
aspect, the pharmaceutical product further comprises a pharmaceutically-acceptable carrier.
In yet other aspects of the pharmaceutical product, the DA-DKP is in a composition
prepared by removing albumin from a solution of a human serum albumin composition. For
example, the step of removing can be by treating the human serum albumin composition by a
separation method. Such separation methods can include ultrafiltration, sucrose gradient
centrifugation, chromatography, salt precipitation, and sonication. In addition, the step of
removing can be by passing the human serum albumin composition over an ultrafiltration
membrane with a molecular weight cut off that retains the albumin, and the resulting filtrate
contains the DA-DKP. In one aspect, the ultrafiltration membrane has a molecular weight cutoff
of less than 50 kDa. In still another aspect, the ultrafiltration membrane has a molecular weight
cut off less than 40 kDa, less than 30 kDa, less than 20 kDa, less than 10 kDa, less than 5 kDa or
less than 3 kDa.
DETAILED DESCRIPTION OF THE INVENTION
The invention provides for a method of treating rhinitis, including but not limited to
infectious rhinitis, allergic rhinitis and nonallergic rhinitis. The method comprises administering
to an animal in need thereof an effective amount of a pharmaceutical composition comprising
DA-DKP.
The invention also provides a pharmaceutical product formulated for administration by a
route such as inhalation, insufflation or nasal administration to the nose. The composition
comprises a DA-DKP containing composition.
Allergic rhinitis is a proinflammatory immune response to outdoor or indoor allergens,
such as dust or pollen. Nonallergic rhinitis is rhinitis that is not triggered by allergens or infectious
agents. Types of nonallergic rhinitis include but are not limited to vasomotor, autonomic,
hormonal, drug-induced, atrophic and gustatory rhinitis and rhinitis medicamentosa.
In order to treat rhinitis, the composition comprising DA-DKP is administered to an
animal in need of treatment. Preferably, the animal is a mammal, such as a rabbit, goat, dog, cat,
horse or human. Most preferably, the animal is a human.
Effective dosage forms, modes of administration and dosage amounts for the compounds
of the invention (i.e., a composition comprising DA-DKP, and preparations comprising a filtrate
of DA-DKP, such as a <5000MW fraction as discussed below) may be determined empirically
using the guidance provided herein. It is understood by those skilled in the art that the dosage
amount will vary with the particular disease or condition to be treated, the severity of the disease
or condition, the route(s) of administration, the duration of the treatment, the identity of any other
drugs being administered to the animal, the age, size and species of the animal, and like factors
known in the medical and veterinary arts. In general, a suitable daily dose of a compound of the
present invention will be that amount of the compound which is the lowest dose effective to
produce a therapeutic effect. However, the daily dosage will be determined by an attending
physician or veterinarian within the scope of sound medical judgment. If desired, the effective
daily dose may be administered as two, three, four, five, six or more sub-doses, administered
separately at appropriate intervals throughout the day. Administration of the compound should be
continued until an acceptable response is achieved. Such an acceptable response may be for
example when the symptoms of rhinitis are reduced and/or when the symptoms of rhinitis are no
longer detected by the subject.
The composition of the present invention may be a pharmaceutical solution having a DA-
DKP concentration range with a lower endpoint of about 10 µM, about 20 µM, about 30 µM,
about 40 µM, about 50 µM, about 60 µM, about 70 µM, about 80 µM, about 90 µM, about 100
µM, about 110 µM, about 120 µM, about 130 µM, about 140 µM, about 150 µM, about 160 µM,
about 170 µM, about 180 µM, about 190 µM, about 200 µM, about 210 µM, about 220 µM, about
230 µM, about 240 µM, about 240, about 250 µM, about 260 µM, about 270 µM, about 280 µM,
about 290 µM, about 300 µM, about 310, about 320 µM, about 330 µM, about 340 µM, about 350
µM, about 360 µM, about 370 µM, about 380 µM, about 390 µM, or about 400 µM. The
composition of the present invention may be a pharmaceutical solution having a DA-DKP
concentration range with an upper endpoint of about 600 µM, about 580 µM, about 570 µM,
about 560 µM, about 550 µM, about 540 µM, about 530 µM, about 520 µM, about 510 µM, about
500 µM, about 490 µM, about 480 µM, about 470 µM, about 460 µM, about 450 µM, about 440
µM, about 430 µM, about 420 µM, about 410 µM, about 400 µM, about 390 µM, about 380 µM,
about 370 µM, about 360 µM, about 350, about 340 µM, about 330 µM, about 320 µM, about 310
µM, about 300 µM, about 290 µM, about 280, about 270 µM, about 260 µM, about 250 µM,
about 240 µM, about 230 µM, about 220 µM, about 210 µM, or about 200 µM.
An effective amount of DA-DKP in the composition of the present invention for treating
rhinitis can be a range with a lower endpoint of about 10 µg, about 15 µg, about 20 µg, about 25
µg, about 30 µg, about 35 µg, about 40 µg, about 45 µg, about 50 µg, about 55 µg, about 60 µg,
about 65 µg, about 70 µg, about 75 µg, about 80 µg, about 85 µg, about 90 µg, about 95 µg, about
100 µg, about 110 µg, about 120 µg, about 130 µg, about 140 µg, about 150 µg, about 160 µg,
about 170 µg, about 180 µg, about 190 µg, about 200 µg, about 210 µg, about 220 µg, about 230
µg, about 240 µg, about 250 µg, about 260 µg, about 270 µg, about 280 µg, about 290 µg, about
300 µg, about 310 µg, about 320 µg, about 330 µg, about 340 µg, about 350 µg, about 360 µg,
about 370 µg, about 380 µg, about 390 µg, about 400 µg, about 425 µg, about 450 µg, about 475
µg or about 500 µg. An effective amount of DA-DKP in the composition of the present invention
for treating rhinitis can be a range with upper endpoint of about 500 µg, about 490 µg, about 480
µg, about 470 µg, about 460 µg, about 450 µg, about 440 µg, about 430 µg, about 420 µg, about
410 µg, about 400 µg, about 390 µg, about 380 µg, about 370 µg, about 360 µg, about 350 µg,
about 340 µg, about 330 µg, about 320 µg, about 310 µg, about 300 µg, about 290 µg, about 280
µg, about 270 µg, about 260 µg, about 250 µg, about 240 µg, about 230 µg, about 220 µg, about
210 µg, about 200 µg, about 190 µg, about 180 µg, about 170 µg, about 160 µg, about 150 µg,
about 140 µg, about 130 µg, about 120 µg, about 110 µg, about 100 µg, about 90 µg, about 80 µg,
about 70 µg, about 60 µg, about 50 µg, about 40 µg, about 30 µg, or about 20 µg.
Additionally, when the DA-DKP containing composition is administered as a spray
composition or formulation and/or as drop composition or formulation, the effective dosage
amounts can be a range with a lower end point of about 0.01% (weight/volume (w/v)), about
0.02% (w/v), about 0.03% (w/v), about 0.04% (w/v), about 0.05% (w/v), about 0.06% (w/v),
about 0.07% (w/v), about 0.08% (w/v), about 0.09% (w/v), about 0.10% (w/v), about 0.11%
(w/v), about 0.12% (w/v), about 0.13% (w/v), about 0.14% (w/v), about 0.15% (w/v), about
0.16% (w/v), about 0.17% (w/v), about 0.18% (w/v), about 0.19% (w/v), about 0.20% (w/v),
about 0.25% (w/v), about 0.30% (w/v), about 0.35% (w/v), about 0.40% (w/v), about 0.45%
(w/v), about 0.50% (w/v). Most preferably about 0.1% (w/v). Also, when the DA-DKP
containing composition is administered as a spray composition or formulation and/or as drop
composition or formulation, the effective dosage amounts can be a range with a upper end point
about 10.0% (w/v), about 9.0% (w/v), about 8.0% (w/v), about 7.0% (w/v), about 6.0% (w/v),
about 5.0% (w/v), about 4.0% (w/v), about 3.0% (w/v), about 2.0% (w/v), 1.0% (w/v), about
0.95% (w/v), about 0.90% (w/v), about 0.85% (w/v), about 0.80% (w/v), about 0.75% (w/v),
about 0.70% (w/v), about 0.65% (w/v), about 0.60% (w/v), or about 0.55% (w/v).
The administration of the DA-DKP containing composition may be commenced within 24
hours of diagnosis of rhinitis. The administration of the DA-DKP containing composition may be
commenced at the appearance of one or more early signs of, or a predisposition to develop,
rhinitis. The early signs of rhinitis include but are not limited torhinorrhea, nasal congestion,
nasal itching and sneezing.
The compounds of the present invention (i.e., a composition comprising DA-DKP, and
preparations comprising a filtrate of DA-DKP, such as a <5000MW fraction as discussed below)
may be administered to an animal patient for therapy by any suitable route of administration,
including orally, nasally, parenterally (e.g., intravenously, intraperitoneally, subcutaneously or
intramuscularly), transdermally, intraocularly and topically (including buccally and sublingually).
Preferred is oral, ocular or nasal administration for any disease or condition treatable according to
the invention. Especially preferred is nasal administration.
While it is possible for a DA-DKP containing composition of the present invention to be
administered alone, it is preferable to administer the DA-DKP containing composition as a
pharmaceutical formulation or product. The pharmaceutical compositions of the invention
comprise a compound or compounds of the invention as an active ingredient in admixture with
one or more pharmaceutically-acceptable carriers and, optionally, with one or more other
compounds, drugs or other materials. Each carrier must be "acceptable" in the sense of being
compatible with the other ingredients of the formulation and not injurious to the animal.
Pharmaceutically-acceptable carriers are well known in the art. Regardless of the route of
administration selected, the DA-DKP containing compositions of the present invention are
formulated into pharmaceutically-acceptable dosage forms by conventional methods known to
those of skill in the art. See, e.g., Remington=s Pharmaceutical Sciences.
Formulations of the invention suitable for oral administration may be in the form of
capsules, cachets, pills, tablets, powders, granules or as a solution or a suspension in an aqueous
or non-aqueous liquid, or an oil-in-water or water-in-oil liquid emulsions, or as an elixir or syrup,
or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia), and the
like, each containing a predetermined amount of a compound or compounds of the present
invention as an active ingredient. Formulations of the present invention may also be administered
as bolus, electuary or paste.
In solid dosage forms of the invention for oral administration (capsules, tablets, pills,
dragees, powders, granules and the like), the active ingredient (i.e., a composition comprising
DA-DKP, and preparations comprising a filtrate of DA-DKP, such as a <5000MW fraction as
discussed below) is mixed with one or more pharmaceutically acceptable carriers, such as sodium
citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as
starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example,
carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3)
humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate,
potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution
retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium
compounds; (7) wetting agents, such as, for example, cetyl alcohol and glycerol monosterate; (8)
absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate,
magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and
(10) coloring agents. In the case of capsules, tablets and pills, the pharmaceutical compositions
may also comprise buffering agents. Solid compositions of a similar type may be employed as
fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as
well as high molecular weight polyethylene glycols and the like.
A tablet may be made by compression or molding optionally with one or more accessory
ingredients. Compressed tablets may be prepared using binder (for example, gelatin or
hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example,
sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or
dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the
powdered compound moistened with an inert liquid diluent.
The tablets, and other solid dosage forms of the pharmaceutical compositions of the
present invention, such as dragees, capsules, pills and granules, may optionally be scored or
prepared with coatings and shells, such as enteric coatings and other coatings well known in the
pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled
release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in
varying proportions to provide the desired release profile, other polymer matrices, liposomes
and/or microspheres. They may be sterilized by, for example, filtration through a bacteria-
retaining filter. These compositions may also optionally contain opacifying agents and may be of
a composition that they release the active ingredient only, or preferentially, in a certain portion of
the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions
which can be used include polymeric substances and waxes. The active ingredient can also be in
microencapsulated form.
Liquid dosage forms for oral administration of the compounds of the invention include
pharmaceutically-acceptable emulsions, microemulsions, solutions, suspensions, syrups and
elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents
commonly used in the art, such as, for example, water or other solvents, solubilizing agents and
emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl
alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed,
groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol,
polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
Besides inert diluents, the oral compositions can also include adjuvants such as wetting
agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and
preservative agents.
Suspensions, in addition to the active ingredient, may contain suspending agents as, for
example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters,
microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and
mixtures thereof.
Pharmaceutical formulations and products include those suitable for administration by
inhalation or insufflation or for nasal administration. For administration to the upper (nasal) or
lower respiratory tract by inhalation, the DA-DKP containing compositions of the invention are
conveniently delivered from a device for inhalation delivery such as an insufflator, nebulizer or a
pressurized pack or other convenient means of delivering an aerosol spray. Pressurized packs
may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized
aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount.
Alternatively, for administration by inhalation or insufflation, the composition may take
the form of a dry powder, for example, a powder mix of the DA-DKP containing composition of
the invention and a suitable powder base, such as lactose or starch. The powder composition may
be presented in unit dosage form in, for example, capsules or cartridges, or, e.g., gelatin or blister
packs from which the powder may be administered with the aid of an inhalator, insufflator or a
metered-dose inhaler.
For nasal administration, DA-DKP containing compositions of the invention may be
administered by means of nose drops or a liquid spray, such as by means of a plastic bottle spray
or atomizer or metered-dose inhaler. Liquid sprays are conveniently delivered from pressurized
packs.
Nose drops may be formulated with an aqueous or nonaqueous base also comprising one
or more dispersing agents, solubilizing agents or suspending agents. Drops can be delivered by
means of a simple eye dropper-capped bottle or by means of a plastic bottle adapted to deliver
liquid contents dropwise by means of a specially shaped closure.
Ointments, gels and creams can also be used for nasal administration of the DA-DKP
containing compositions of the invention. The active ingredient may be mixed under sterile
conditions with a pharmaceutically-acceptable carrier, and with any buffers, or propellants which
may be required. The ointments, creams and gels may contain, in addition to the active
ingredient, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth,
cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide,
or mixtures thereof.
Dosage forms for topical administration or for transdermal administration of compounds
of the invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions,
patches, drops and inhalants. The active ingredient may be mixed under sterile conditions with a
pharmaceutically-acceptable carrier, and with any buffers, or propellants which may be required.
The ointments, pastes, creams and gels may contain, in addition to the active ingredient,
excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose
derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or
mixtures thereof. Powders and sprays can contain, in addition to the active ingredient, excipients
such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder or
mixtures of these substances. Sprays can additionally contain customary propellants such as
chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
Transdermal patches have the added advantage of providing controlled delivery of compounds of
the invention to the body. Such dosage forms can be made by dissolving, dispersing or otherwise
incorporating one or more compounds of the invention in a proper medium, such as an
elastomeric matrix material. Absorption enhancers can also be used to increase the flux of the
compound across the skin. The rate of such flux can be controlled by either providing a rate-
controlling membrane or dispersing the compound in a polymer matrix or gel. A drug-
impregnated solid carrier (e.g., a dressing) can also be used for topical administration.
Pharmaceutical compositions of this invention suitable for parenteral administrations
comprise one or more compounds of the invention in combination with one or more
pharmaceutically-acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions,
suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable
solutions or dispersions just prior to use, which may contain antioxidants, buffers, solutes which
render the formulation isotonic with the blood of the intended recipient or suspending or
thickening agents. Also, drug-coated stents may be used.
Examples of suitable aqueous and nonaqueous carriers which may be employed in the
pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol,
propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils,
such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be
maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of
the required particle size in the case of dispersions, and by the use of surfactants.
These compositions may also contain adjuvants such as wetting agents, emulsifying agents
and dispersing agents. It may also be desirable to include isotonic agents, such as sugars, sodium
chloride, and the like in the compositions. In addition, prolonged absorption of the injectable
pharmaceutical form may be brought about by the inclusion of agents which delay absorption
such as aluminum monosterate and gelatin.
In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption
of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use
of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate
of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend
upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally-
administered drug is accomplished by dissolving or suspending the drug in an oil vehicle.
Injectable depot forms are made by forming microencapsule matrices of the drug in
biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to
polymer, and the nature of the particular polymer employed, the rate of drug release can be
controlled. Examples of other biodegradable polymers include poly(orthoesters) and
poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in
liposomes or microemulsions which are compatible with body tissue. The injectable materials
can be sterilized for example, by filtration through a bacterial-retaining filter.
The formulations may be presented in unit-dose or multi-dose sealed containers, for
example, ampules and vials, and may be stored in a lyophilized condition requiring only the
addition of the sterile liquid carrier, for example water for injection, immediately prior to use.
Extemporaneous injection solutions and suspensions may be prepared from sterile powders,
granules and tablets of the type described above.
While it is possible for a DA-DKP containing composition to be given alone to treat
rhinitis, alternatively, the DA-DKP containing composition may be given in combination with one
or more other treatments or drugs suitable for treating the rhinitis. For instance, the DA-DKP
containing composition can be administered prior to, in conjunction with (including
simultaneously with), or after the other treatment or drug. In the case of another drug, the drug
and the DA-DKP containing composition may be administered in separate pharmaceutical
compositions or as part of the same pharmaceutical composition. Suitable other drugs include
antihistamines, decongestants, anti-inflammatories (steroidal and nonsteroidal), mast cell
stabilizers, leukotriene modifiers and IgE blockers. Specific suitable drugs include fexofenadine,
doxylamine, diphenhydramine, triprolidine, loratidine, cetirizine, pseudophedrine, phenylephrine,
aspirin, ibuprofen, naproxen, prednisone, prednisolone, and methylprednisolone. Suitable drugs
for inclusion in a nasal spray are steroids (such as fluticasone propionate, mometasone,
budesonite, flunisolide, triamcinolone and beclomethasone), antihistamines (such as azelastine),
anticholinergics (such as ipratproium) and mast cell stabilizers (such as cromolyn).
Methods of making diketopiperazines, such as DA-DKP, are well known in the art, and
these methods may be employed to synthesize the diketopiperazines of the invention. See, e.g.,
U.S. Patents Nos. 4,694,081, 5,817,751, 5,990,112, 5,932,579, 6,555,543; US Patent Application
Publication Number 2004/0024180, PCT applications WO 96/00391 and WO 97/48685, and
Smith et al., Bioorg. Med. Chem. Letters, 8, 2369-2374 (1998), the complete disclosures of which
are incorporated herein by reference.
For instance, diketopiperazines, such as DA-DKP, can be prepared by first synthesizing
dipeptides. The dipeptides can be synthesized by methods well known in the art using L-amino
acids, D-amino acids or a combination of D- and L-amino acids. Preferred are solid-phase
peptide synthetic methods. Of course, dipeptides are also available commercially from numerous
sources, including DMI Synthesis Ltd., Cardiff, UK (custom synthesis), Sigma-Aldrich, St. Louis,
MO (primarily custom synthesis), Phoenix Pharmaceuticals, Inc., Belmont, CA (custom
synthesis), Fisher Scientific (custom synthesis) and Advanced ChemTech, Louisville, KY.
Once the dipeptide is synthesized or purchased, it is cyclized to form a diketopiperazine.
This can be accomplished by a variety of techniques. For example, U.S. Patent Application
Publication Number 2004/0024180 describes a method of cyclizing dipeptides. Briefly, the
dipeptide is heated in an organic solvent while removing water by distillation. Preferably, the
organic solvent is a low-boiling azeotrope with water, such as acetonitrile, allyl alcohol, benzene,
benzyl alcohol, n-butanol, 2-butanol, t-butanol, acetic acid butylester, carbon tetrachloride,
chlorobenzene chloroform, cyclohexane, 1,2-dichlorethane, diethylacetal, dimethylacetal, acetic
acid ethylester, heptane, methylisobutylketone, 3-pentanol, toluene and xylene. The temperature
depends on the reaction speed at which the cyclization takes place and on the type of azeotroping
agent used. The reaction is preferably carried out at 50-200 C, more preferably 80-150 C. The
pH range in which cyclization takes place can be easily determine by the person skilled in the art.
It will advantageously be 2-9, preferably 3-7.
When one or both of the amino acids of the dipeptide has, or is derivatized to have, a
carboxyl group on its side chain (e.g., aspartic acid or glutamic acid), the dipeptide is preferably
cyclized as described in U.S. Patent No. 6,555,543. Briefly, the dipeptide, with the side-chain
carboxyl still protected, is heated under neutral conditions. Typically, the dipeptide will be
o o o
heated at from about 80 C to about 180 C, preferably at about 120 C. The solvent will be a
neutral solvent. For instance, the solvent may comprise an alcohol (such as butanol, methanol,
ethanol, and higher alcohols, but not phenol) and an azeotropic co-solvent (such as toluene,
benzene, or xylene). Preferably, the alcohol is butanol, and the azeotropic co-solvent is
toluene. The heating is continued until the reaction is complete, and such times can be
determined empirically. Typically, the dipeptide will be cyclized by refluxing it for about 8-24
hours, preferably about 18 hours. Finally, the protecting group is removed from the
diketopiperazine. In doing so, the use of strong acids (mineral acids, such as sulfuric or
hydrochloric acids), strong bases (alkaline bases, such as potassium hydroxide or sodium
hydroxide), and strong reducing agents (e.g., lithium aluminum hydride) should be avoided, in
order to maintain the chirality of the final compound.
Dipeptides made on solid phase resins can be cyclized and released from the resin in one
step. See, e.g., U.S. Patent No. 5,817,751. For instance, the resin having an N-alkylated
dipeptide attached is suspended in toluene or toluene/ethanol in the presence of acetic acid (e.g.,
1%) or triethylamine (e.g., 4%). Typically, basic cyclization conditions are preferred for their
faster cyclization times.
Other methods of cyclizing dipeptides and of making diketopiperazines are known in the
art and can be used in the preparation of diketopiperazines useful in the practice of the invention.
See, e.g., those references listed above. In addition, many diketopiperazines suitable for use in the
present invention can be made as described below from proteins and peptides. Further,
diketopiperazines for use in the practice of the invention can be obtained commercially from, e.g.,
DMI Synthesis Ltd., Cardiff, UK (custom synthesis).
The DA-DKP composition and/or products of the present invention can be prepared from
solutions containing DA-DKP, including from the commercially-available pharmaceutical
compositions comprising albumin, such as human serum albumin, by well known methods, such
as ultrafiltration, chromatography ( size-exclusion chromatography (e.g., Centricon filtration),
affinity chromatography (e.g., using a column of beads having attached thereto an antibody or
antibodies directed to the desired diketopiperazine(s) or an antibody or antibodies directed to the
truncated protein or peptide), anion exchange or cation exchange), sucrose gradient
centrifugation, chromatography, salt precipitation, or sonication, that will remove some or all of
the albumin in the solution. The resultant DA-DKP-containing composition and/or product can
be used and incorporated into pharmaceutical compositions as described above.
Using an ultrafilration separation method, a human serum albumin composition can be
passed over an ultrafiltration membrane having a molecular weight cut-off that retains the
albumin while the DA-DKP passes into the resulting filtrate or fraction. This filtrate may
comprise components having molecular weights less than about 50 kDA, less than about 40 kDa,
less than 30 kDa, less than about 20 kDa, less than about 10 kDa, less than about 5 kDa, less than
about 3 kDa. Preferably, the filtrate comprises components having molecular weights less than
about 5 kDa (also referred to as “<5000MW”). This <5000MW fraction or filtrate contains
DA-DKP which is formed after the dipeptide aspartate-alanine is cleaved from albumin and
subsequently cyclized into the diketopiperazine. The <5000MW Fraction can be prepared as
described in U.S. Patent No. 7,732,403, the complete disclosure of which is incorporated herein
by reference.
Physiologically-acceptable salts of the DA-DKP of the invention may also be used in the
practice of the invention. Physiologically-acceptable salts include conventional non-toxic salts,
such as salts derived from inorganic acids (such as hydrochloric, hydrobromic, sulfuric,
phosphoric, nitric, and the like), organic acids (such as acetic, propionic, succinic, glycolic,
stearic, lactic, malic, tartaric, citric, glutamic, aspartic, benzoic, salicylic, oxalic, ascorbic acid,
and the like) or bases (such as the hydroxide, carbonate or bicarbonate of a pharmaceutically-
acceptable metal cation or organic cations derived from N,N-dibenzylethylenediamine, D-
glucosamine, or ethylenediamine). The salts are prepared in a conventional manner, e.g., by
neutralizing the free base form of the compound with an acid.
Kits comprising the pharmaceutical products of the present invention are also provided.
The kits can comprise a DA-DKP composition formulated for nasal administration. The DA-
DKP can be prepared as described herein, such as by removing albumin from a solution of a
human albumin composition. The kits may contain unit-dose or multi-dose sealed containers, for
example, squeeze bottles, syringes, a dropper, a spray device, an atomizer device, an aerosolize, a
nebulizer, an insufflators or pressurized packs. The kits may be stored in a condition, wherein the
contents are ready for direct use. Alternately, the kits may be stored in a lyophilized condition
requiring only the addition of the sterile liquid carrier, for example water, immediately prior to
use.
As used herein, "a" or "an" means one or more.
As used herein, "comprises" and "comprising" include within their scope all narrower
terms, such as "consisting essentially of" and "consisting of" as alternative embodiments of the
present invention characterized herein by "comprises" or "comprising". In regard to use of
"consisting essentially of", this phrase limits the scope of a claim to the specified steps and
materials and those that do not materially affect the basic and novel characteristics of the
invention disclosed herein. .
Additional objects, advantages and novel features of the present invention will become
apparent to those skilled in the art by consideration of the following non-limiting examples. The
following experimental results are provided for purposes of illustration and are not intended to
limit the scope of the invention.
EXAMPLE
A Phase Ib randomized, double-blinded, placebo-controlled, parallel group study was
performed to evaluate the efficacy of the <5000MW Fraction for treating allergic rhinitis in adult
humans. Briefly, the study was performed as follows.
The subjects were male or female humans, 18-65 years of age, with a history of allergic
rhinitis that had been receiving therapy (continuous or intermittent) for more than 1 year. Each
subject had a demonstrated sensitivity to at least one seasonal allergen (tree/grass pollen) known
to induce allergic rhinitis through a standard skin test. Each subject had a minimum subject-
reported reflective Total Nasal Symptom Score (rTNSS) of > 5 on the day of the Screening Visit
(day 1).
During a seven-day wash out period (days 1-7), the subjects received no treatment of any
type and recorded their symptoms twice a day (in the morning before bathing, consumption of
food or beverages or strenuous activities and 12 hours later) using the following scale:
• 0 = absent (no sign/symptom present)
• 1 = mild (sign/symptom clearly present, but minimal awareness; easily tolerated)
• 2 = moderate (definite awareness of sign/symptom that is bothersome but
tolerable)
• 3 = severe (sign/symptom that is hard to tolerate; causes interference with
activities of daily living and/or sleeping)
The subjects were randomized into treatment groups (<5000MW Fraction or placebo (i.e.
saline)) after the wash out period (on day 8).
Treatment was begun on day 8 and continued through day 17 (10 days total). During
treatment, the subjects again recorded their symptoms twice daily (as described above and before
administration of the test medications in the morning) using the above scale. The subjects
administered 0.3 ml of one of the test medications, 0.15 ml per nostril, once daily in the morning,
immediately after recording their symptoms. The first administration of test medications was
supervised by test site personnel. The test medications were the <5000MW Fraction (containing
3.72% DA-DKP) used as a nasal spray and placebo spray (containing normal saline, 0.9% NaCl)
in identical intranasal spray format.
Efficacy of the test medications was assessed as follows:
The measures of effectiveness in this study included the subject-reported Total Nasal
Symptom Score (TNSS). The TNSS is defined as the sum of the subject-reported symptom
scores for the four nasal symptoms: rhinorrhea (runny nose), nasal congestion, nasal itching, and
sneezing. Each score is assessed on a severity scale ranging from 0 to 3 as defined above.
The subjects were asked to assess both reflective TNSS (i.e., an evaluation of symptom
severity over the past 12 hours prior to the recording of the score) and instantaneous TNSS (i.e.,
an evaluation of the symptom severity over the last 10 minutes).
The reflective and instantaneous TNSS are defined as the sum of the subject-reported
symptom scores for the four nasal symptoms. Each subject recorded the symptom scores in the
subject’s diary. For each score, information recorded in the diary included the following:
• rhinorrhea (runny nose)
• nasal congestion
• nasal itching
• sneezing
The severity scale for each symptom evaluation is given above.
Mean reflective (r) and instantaneous (i) subject-reported total nasal symptom scores
(TNSS) were calculated for each subject. The mean TNSS is the average of all AM and PM daily
scores (each score is ranked on a scale from 0-12) during the baseline (baseline efficacy value)
and the treatment period (double-blind efficacy value).
The change in efficacy was calculated as the change in the double-blind value – baseline
value as follows:
Change in rTNSS: mean double-blind rTNSS – mean baseline rTNSS
Change in iTNSS: mean double-blind iTNSS – mean baseline iTNSS
Student’s t-test: mean (SD) difference between treatment groups for the following:
Mean change in (rTNSS/iTNSS)
Mean change in AM (rTNSS/iTNSS)
Mean change in PM (rTNSS/iTNSS)
Mean change in individual symptom scores for each of the four nasal
symptoms.
The results obtained by analysis using the Student’s t-test are provided in Tables 1-5 and
are summarized below (number of subjects who completed the trial at the time of the interim
analysis: n=20; placebo, n=10 (Intent to Treat (ITT) population; >5000MW Fraction, n=10 (ITT
population).
rTNSS: <5000MW Fraction showed a 2.4 point decrease in reflective symptom severity
compared to 1.7 point decrease with placebo (Table 2). There was 35% improvement in rTNSS
with <5000MW Fraction versus 23% improvement with placebo. The largest improvements were
with sneezing and runny nose symptoms (Table 3). 6/7 efficacy measures showed a larger
improvement with <5000MW Fraction than placebo (all assessments but itchy nose symptom).
There was significant rTNSS improvement in subset with baseline rTNSS < median (7.5).
Table 1 Baseline efficacy variables, mean (SD)
Efficacy Variable Placebo <5000MW T-test p value
Fraction
rTNSS 7.46 (1.71) 6.84 (1.39) 0.39
iTNSS 7.40 (1.71) 6.45 (1.11) 0.16
PNSS (screening) 6.50 (1.43) 5.60 (1.65) 0.21
PNSS 6.90 (1.60) 5.50 (0.85)
0.03
(randomization)
PNSS = Physician Nasal Symptoms Score; TNSS = Total Nasal Symptoms Score
Table 2 Mean change in rTNSS
Efficacy Saline n=10 <5000MW T-test p value
Variable Mean (SD) Fraction n=10 (SD)
rTNSS -1.71 (1.82) -2.37 (2.06) 0.46
AM rTNSS -1.68 (1.69) -2.25 (2.00) 0.51
PM rTNSS -1.72 (1.95) -2.03 (2.08) 0.74
Table 3 Mean Change in Reflective Symptoms
Symptom Saline n=10 <5000MW T-test p value
Mean (SD) Fraction n=10 (SD)
rRunny nose -0.33 (0.8) -0.60 (0.8) 0.45
rStuffy nose -0.58 (0.6) -0.59 (0.5) 0.97
rItchy nose -0.54 (0.6) -0.53 (0.6) 0.97
rSneezing -0.26 (0.3) -0.65 (0.7) 0.13
iTNSS: <5000MW Fraction showed a 2.0 point decrease in instantaneous symptom
severity compared to 1.7 point decrease with placebo (Table 4). 5/7 efficacy measures showed a
larger improvement with <5000MW Fraction than with placebo. The largest improvements were
with sneezing nose symptoms (Table 5). Smaller improvements were seen with instantaneous
versus reflective symptoms.
Table 4 Mean Change in iTNSS
Efficacy Saline n=10 <5000MW T-test p value
variable Mean (SD) Fraction n=10 (SD)
iTNSS -1.68 (1.84) -1.97 (2.06) 0.75
AM iTNSS -1.55 (1.69) -1.84 (1.94) 0.73
PM iTNSS -1.50 (1.61) -1.56 (1.98) 0.94
Table 5 Mean Change in Instantaneous Symptoms
Symptom Placebo <5000MW T-test p value
Mean (SD) Fraction (SD)
iRunny nose -0.27 (0.8) -0.37 (0.8) 0.78
iStuffy nose -0.54 (0.4) -0.53 (0.6) 0.98
iItchy nose -0.63 (0.6) -0.46 (0.6) 0.53
iSneezing -0.24 (0.6) -0.61 (0.5) 0.16
While various embodiments of the present invention have been described in detail, it is
apparent that modifications and adaptations of those embodiments will occur to those skilled in
the art. It is to be expressly understood, however, that such modifications and adaptations are
within the scope of the present invention, as set forth in the following exemplary claims.
Claims (27)
1. A use of an effective amount of a pharmaceutical composition comprising a diketopiperazine with amino acid side chains of aspartic acid and alanine (DA-DKP) in the manufacture of a medicament for the treatment of rhinitis, wherein the DA-DKP comprises from about 0.1% (w/v) to about 10% (w/v) of the composition.
2. The use of Claim 1, wherein the rhinitis is allergic rhinitis.
3. The use of Claim 1, wherein the effective amount of the DA-DKP in the composition is from about 100 µg to about 3000 µg per day.
4. The use of Claim 1, wherein the effective amount of the DA-DKP in the composition is from about from about 500 µg to about 1500 µg per day.
5. The use of Claim 1, wherein treatment is commenced within 24 hours of diagnosis of rhinitis.
6. The use of Claim 1, wherein treatment is commenced at the appearance of one or more early signs of, or a predisposition to develop, rhinitis.
7. The use of Claim 6, wherein the one or more early signs of rhinitis are selected from the group consisting of rhinorrhea, nasal congestion, nasal itching and sneezing.
8. The use of Claim 1, wherein the DA-DKP is in a composition prepared by removing albumin from a solution of a human serum albumin composition.
9. The use of Claim 8, wherein the step of removing the albumin comprises treating the human serum albumin composition by a separation method selected from the group consisting of ultrafiltration, sucrose gradient centrifugation, chromatography, salt precipitation, and sonication.
10. The use of Claim 9, wherein the step of removing comprises passing the human serum albumin composition over an ultrafiltration membrane with a molecular weight cut off that retains the albumin, and wherein the resulting filtrate comprises DA-DKP.
11. The use of Claim 10, wherein the ultrafiltration membrane has molecular weight cutoff of less than 50 kDa, less than 40 kDa, less than 30 kDA, less than 20 kDa, less than 10 kDa, less than 5 kDa or less than 3 kDA.
12. The use of Claim 1, wherein the composition comprising DA-DKP also includes a second drug suitable for treating rhinitis.
13. The use of Claim 12, wherein the second drug suitable for treating rhinitis is selected from the group consisting of antihistamines, decongestants, anti-inflammatories, mast cell stabilizers, leukotriene modifiers and IgE blockers.
14. A pharmaceutical product, comprising a DA-DKP containing composition formulated for nasal administration to the nose in a form of drops or sprays, wherein the DA-DKP comprises from about 0.1% (w/v) to about 10% (w/v) of the composition and wherein the DA-DKP is prepared by removing albumin from a solution of a human serum albumin composition comprising passing the human serum albumin composition over an ultrafiltration membrane with a molecular weight cut off that retains the albumin, and wherein the resulting filtrate comprises DA-DKP.
15. The pharmaceutical product of Claim 14, wherein the DA-DKP containing composition is packaged in a device selected from the group consisting of insufflators, nebulizers, pressurized packs, squeeze bottle, a syringe, a dropper, a spray device, an atomizer device, and an aerosolizer.
16. The pharmaceutical product of Claim 15, wherein the pressurized pack comprises a propellant selected from the group consisting of dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, and carbon dioxide.
17. The pharmaceutical product of Claim 14, wherein the drops or sprays are contained within an intranasal delivery system.
18. The pharmaceutical product of Claim 17 wherein the intranasal delivery system comprises an atomizing device.
19. The pharmaceutical product of Claim 18 wherein the atomizing device comprises a bottle and a pump.
20. The pharmaceutical product of Claim 19 wherein the pump is a metered dose pump.
21. The pharmaceutical product of Claim 20 wherein the metered dose pump delivers an intranasal volume of the DA-DKP containing composition of about 0.15 ml per pump.
22. The pharmaceutical product of Claim 14, further comprising an aqueous or non- aqueous base comprising one or more agents selected from the group consisting of dispersing agents, solubilizing agents, and suspending agents.
23. The pharmaceutical product of Claim 14, wherein the DA-DKP containing composition further comprises excipients selected from the group consisting of animal fats, vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicones, bentonites, silicic acid, talc, zinc oxide and mixtures thereof.
24. The pharmaceutical product of Claim 14, further comprising an absorption or permeation enhancer.
25. The pharmaceutical product of Claim 14, further comprising a thickening agent or viscosity enhancer to increase the residence time of the DA-DKP containing composition in the nose.
26. The pharmaceutical product of Claim 14, further comprising a pharmaceutically- acceptable carrier.
27. The pharmaceutical product of Claim 14, wherein the ultrafiltration membrane has molecular weight cutoff of less than 50 kDa, less than 40 kDa, less than 30 kDA, less than 20 kDa, less than 10 kDa, less than 5 kDa or less than 3 kDA.
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161552508P | 2011-10-28 | 2011-10-28 | |
US61/552,508 | 2011-10-28 | ||
US201161561215P | 2011-11-17 | 2011-11-17 | |
US61/561,215 | 2011-11-17 | ||
PCT/US2012/062152 WO2013063413A1 (en) | 2011-10-28 | 2012-10-26 | Treatment of rhinitis |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ623879A NZ623879A (en) | 2016-03-31 |
NZ623879B2 true NZ623879B2 (en) | 2016-07-01 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10881710B2 (en) | Treatment of rhinitis | |
US8758816B2 (en) | Compositions comprising azelastine and methods of use thereof | |
AU2004241101B2 (en) | Treatment of T-cell mediated diseases | |
DK2377557T3 (en) | Compositions comprising azelastine and methods for its use | |
JP6203734B2 (en) | Treatment of osteoarthritis | |
US20070020330A1 (en) | Compositions comprising azelastine and methods of use thereof | |
RU2736513C2 (en) | Treating pathological conditions of joints | |
KR20120100887A (en) | Methods for treatment of pain | |
WO2007061454A1 (en) | Compositions comprising azelastine and methods of use thereof | |
US11478441B2 (en) | Treatment of disease with n-acetyl kynurenine | |
RU2008146733A (en) | A NEW APPROACH TO TREATMENT OF INCREASED IN-ORGAL PRESSURE | |
KR20190055057A (en) | Composition, apparatus and method for the treatment of alcohol use disorders | |
AU2012318411A1 (en) | Treatment of rhinitis | |
NZ623879B2 (en) | Treatment of rhinitis | |
AU2013270553B2 (en) | Treatment of t-cell mediated diseases |