IE83747B1 - Non-chlorofluorocarbon aerosol formulations - Google Patents
Non-chlorofluorocarbon aerosol formulationsInfo
- Publication number
- IE83747B1 IE83747B1 IE1992/1847A IE921847A IE83747B1 IE 83747 B1 IE83747 B1 IE 83747B1 IE 1992/1847 A IE1992/1847 A IE 1992/1847A IE 921847 A IE921847 A IE 921847A IE 83747 B1 IE83747 B1 IE 83747B1
- Authority
- IE
- Ireland
- Prior art keywords
- fatty acids
- chain fatty
- medium chain
- alcohols
- menthol
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims description 48
- 239000000443 aerosol Substances 0.000 title claims description 16
- 239000003380 propellant Substances 0.000 claims description 36
- 239000003814 drug Substances 0.000 claims description 35
- YFMFNYKEUDLDTL-UHFFFAOYSA-N 1,1,1,2,3,3,3-Heptafluoropropane Chemical compound FC(F)(F)C(F)C(F)(F)F YFMFNYKEUDLDTL-UHFFFAOYSA-N 0.000 claims description 26
- 239000004094 surface-active agent Substances 0.000 claims description 24
- 150000004667 medium chain fatty acids Chemical class 0.000 claims description 21
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 19
- -1 triglyceride esters Chemical class 0.000 claims description 18
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N Oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims description 16
- 238000009472 formulation Methods 0.000 claims description 16
- 150000001298 alcohols Chemical class 0.000 claims description 13
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 claims description 11
- 229960004873 LEVOMENTHOL Drugs 0.000 claims description 11
- 229940041616 Menthol Drugs 0.000 claims description 11
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 11
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 11
- 239000000194 fatty acid Substances 0.000 claims description 11
- 150000004665 fatty acids Chemical class 0.000 claims description 11
- WOFMFGQZHJDGCX-ZULDAHANSA-N Mometasone furoate Chemical compound O([C@]1([C@@]2(C)C[C@H](O)[C@]3(Cl)[C@@]4(C)C=CC(=O)C=C4CC[C@H]3[C@@H]2C[C@H]1C)C(=O)CCl)C(=O)C1=CC=CO1 WOFMFGQZHJDGCX-ZULDAHANSA-N 0.000 claims description 10
- 229960002744 mometasone furoate Drugs 0.000 claims description 10
- 239000005642 Oleic acid Substances 0.000 claims description 8
- 239000002245 particle Substances 0.000 claims description 8
- 239000002202 Polyethylene glycol Substances 0.000 claims description 7
- 229920001223 polyethylene glycol Polymers 0.000 claims description 7
- 150000004666 short chain fatty acids Chemical class 0.000 claims description 7
- 235000021391 short chain fatty acids Nutrition 0.000 claims description 7
- 208000006673 Asthma Diseases 0.000 claims description 6
- 229940044949 Eucalyptus oil Drugs 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- 239000010642 eucalyptus oil Substances 0.000 claims description 6
- TXGPGHBYAPBDAG-UHFFFAOYSA-N 1,1,2,2,3,3-hexafluoro-4,4-bis(trifluoromethyl)cyclobutane Chemical compound FC(F)(F)C1(C(F)(F)F)C(F)(F)C(F)(F)C1(F)F TXGPGHBYAPBDAG-UHFFFAOYSA-N 0.000 claims description 5
- 229920001213 Polysorbate 20 Polymers 0.000 claims description 5
- 229920001214 Polysorbate 60 Polymers 0.000 claims description 5
- 239000004147 Sorbitan trioleate Substances 0.000 claims description 5
- 229960000391 Sorbitan trioleate Drugs 0.000 claims description 5
- PRXRUNOAOLTIEF-XDTJCZEISA-N [2-[(2R,3S,4R)-4-hydroxy-3-[(Z)-octadec-9-enoyl]oxyoxolan-2-yl]-2-[(Z)-octadec-9-enoyl]oxyethyl] (Z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CCCCCCCC)[C@H]1OC[C@@H](O)[C@@H]1OC(=O)CCCCCCC\C=C/CCCCCCCC PRXRUNOAOLTIEF-XDTJCZEISA-N 0.000 claims description 5
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 claims description 5
- 235000019337 sorbitan trioleate Nutrition 0.000 claims description 5
- 239000008347 soybean phospholipid Substances 0.000 claims description 5
- 239000004359 castor oil Substances 0.000 claims description 4
- 235000019438 castor oil Nutrition 0.000 claims description 4
- 125000005456 glyceride group Chemical group 0.000 claims description 4
- 230000002335 preservative Effects 0.000 claims description 4
- 239000003755 preservative agent Substances 0.000 claims description 4
- 150000003626 triacylglycerols Chemical class 0.000 claims description 4
- 239000003963 antioxidant agent Substances 0.000 claims description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M buffer Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 3
- 239000006185 dispersion Substances 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 235000003599 food sweetener Nutrition 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 239000003765 sweetening agent Substances 0.000 claims description 3
- 239000006068 taste-masking agent Substances 0.000 claims description 3
- BVDRUCCQKHGCRX-UHFFFAOYSA-N 2,3-dihydroxypropyl formate Chemical compound OCC(O)COC=O BVDRUCCQKHGCRX-UHFFFAOYSA-N 0.000 claims description 2
- 229960001664 Mometasone Drugs 0.000 claims description 2
- NWGKJDSIEKMTRX-HSACVWGTSA-N [(2R)-2-[(2R,3R,4S)-3,4-dihydroxyoxolan-2-yl]-2-hydroxyethyl] (E)-octadec-9-enoate Chemical compound CCCCCCCC\C=C\CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-HSACVWGTSA-N 0.000 claims description 2
- 230000000111 anti-oxidant Effects 0.000 claims description 2
- 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 claims description 2
- 235000011069 sorbitan monooleate Nutrition 0.000 claims description 2
- 239000001593 sorbitan monooleate Substances 0.000 claims description 2
- 229940035049 sorbitan monooleate Drugs 0.000 claims description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims 5
- 239000002253 acid Substances 0.000 claims 3
- SMNDYUVBFMFKNZ-UHFFFAOYSA-N 2-Furoic acid Chemical compound OC(=O)C1=CC=CO1 SMNDYUVBFMFKNZ-UHFFFAOYSA-N 0.000 claims 2
- 240000001200 Eucalyptus globulus Species 0.000 claims 2
- 235000004694 Eucalyptus leucoxylon Nutrition 0.000 claims 2
- 235000010705 Eucalyptus maculata Nutrition 0.000 claims 2
- 235000009683 Eucalyptus polybractea Nutrition 0.000 claims 2
- 235000009687 Eucalyptus sargentii Nutrition 0.000 claims 2
- 235000001612 eucalyptus Nutrition 0.000 claims 2
- 235000001617 eucalyptus Nutrition 0.000 claims 2
- 235000001621 eucalyptus Nutrition 0.000 claims 2
- 235000006356 eucalyptus Nutrition 0.000 claims 2
- 239000000843 powder Substances 0.000 claims 2
- 235000005227 red mallee Nutrition 0.000 claims 2
- 239000003921 oil Substances 0.000 claims 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 claims 1
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 description 14
- NDAUXUAQIAJITI-UHFFFAOYSA-N Salbutamol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-UHFFFAOYSA-N 0.000 description 11
- 229960002052 salbutamol Drugs 0.000 description 11
- 229940023808 Albuterol Drugs 0.000 description 10
- 229920001400 block copolymer Polymers 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- LVGUZGTVOIAKKC-UHFFFAOYSA-N 1,1,1,2-Tetrafluoroethane Chemical compound FCC(F)(F)F LVGUZGTVOIAKKC-UHFFFAOYSA-N 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- XXJWXESWEXIICW-UHFFFAOYSA-N 2-(2-Ethoxyethoxy)ethanol Chemical compound CCOCCOCCO XXJWXESWEXIICW-UHFFFAOYSA-N 0.000 description 5
- 230000003182 bronchodilatating Effects 0.000 description 5
- 229960001927 Cetylpyridinium Chloride Drugs 0.000 description 4
- YMKDRGPMQRFJGP-UHFFFAOYSA-M Cetylpyridinium chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCC[N+]1=CC=CC=C1 YMKDRGPMQRFJGP-UHFFFAOYSA-M 0.000 description 4
- 229960004063 Propylene glycol Drugs 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 4
- 230000003000 nontoxic Effects 0.000 description 4
- 231100000252 nontoxic Toxicity 0.000 description 4
- CBENFWSGALASAD-UHFFFAOYSA-N ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 4
- 235000013772 propylene glycol Nutrition 0.000 description 4
- HBXWUCXDUUJDRB-UHFFFAOYSA-N 1-octadecoxyoctadecane Chemical compound CCCCCCCCCCCCCCCCCCOCCCCCCCCCCCCCCCCCC HBXWUCXDUUJDRB-UHFFFAOYSA-N 0.000 description 3
- KUVIULQEHSCUHY-XYWKZLDCSA-N Beclometasone dipropionate 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)COC(=O)CC)(OC(=O)CC)[C@@]1(C)C[C@@H]2O KUVIULQEHSCUHY-XYWKZLDCSA-N 0.000 description 3
- 229940092703 Beclomethasone Dipropionate Drugs 0.000 description 3
- BCCOBQSFUDVTJQ-UHFFFAOYSA-N Octafluorocyclobutane Chemical compound FC1(F)C(F)(F)C(F)(F)C1(F)F BCCOBQSFUDVTJQ-UHFFFAOYSA-N 0.000 description 3
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 3
- 230000000240 adjuvant Effects 0.000 description 3
- 229950000210 beclometasone dipropionate Drugs 0.000 description 3
- 125000004432 carbon atoms Chemical group C* 0.000 description 3
- 229940075557 diethylene glycol monoethyl ether Drugs 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 235000019407 octafluorocyclobutane Nutrition 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- JWZZKOKVBUJMES-UHFFFAOYSA-N 4-{1-hydroxy-2-[(propan-2-yl)amino]ethyl}benzene-1,2-diol Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 description 2
- 210000004072 Lung Anatomy 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- XDRYMKDFEDOLFX-UHFFFAOYSA-N Pentamidine Chemical compound C1=CC(C(=N)N)=CC=C1OCCCCCOC1=CC=C(C(N)=N)C=C1 XDRYMKDFEDOLFX-UHFFFAOYSA-N 0.000 description 2
- 229960004448 Pentamidine Drugs 0.000 description 2
- 229920002359 Tetronic® Polymers 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 230000003110 anti-inflammatory Effects 0.000 description 2
- 230000000712 assembly Effects 0.000 description 2
- 239000000168 bronchodilator agent Substances 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- PWEOPMBMTXREGV-UHFFFAOYSA-N decanoic acid;octanoic acid;propane-1,2-diol Chemical compound CC(O)CO.CCCCCCCC(O)=O.CCCCCCCC(O)=O.CCCCCCCCCC(O)=O.CCCCCCCCCC(O)=O PWEOPMBMTXREGV-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drugs Drugs 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 125000001145 hydrido group Chemical group *[H] 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 229960001317 isoprenaline Drugs 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 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 description 1
- HMFKFHLTUCJZJO-UHFFFAOYSA-N 2-{2-[3,4-bis(2-hydroxyethoxy)oxolan-2-yl]-2-(2-hydroxyethoxy)ethoxy}ethyl dodecanoate Chemical compound CCCCCCCCCCCC(=O)OCCOCC(OCCO)C1OCC(OCCO)C1OCCO HMFKFHLTUCJZJO-UHFFFAOYSA-N 0.000 description 1
- 229940035676 ANALGESICS Drugs 0.000 description 1
- 229940057282 Albuterol Sulfate Drugs 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 229940064005 Antibiotic throat preparations Drugs 0.000 description 1
- 229940083879 Antibiotics FOR TREATMENT OF HEMORRHOIDS AND ANAL FISSURES FOR TOPICAL USE Drugs 0.000 description 1
- 229940042052 Antibiotics for systemic use Drugs 0.000 description 1
- 229940042786 Antitubercular Antibiotics Drugs 0.000 description 1
- 241000349774 Bikinia letestui Species 0.000 description 1
- XWTYSIMOBUGWOL-UHFFFAOYSA-N Bricaril Chemical compound CC(C)(C)NCC(O)C1=CC(O)=CC(O)=C1 XWTYSIMOBUGWOL-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 229940064701 Corticosteroid nasal preparations for topical use Drugs 0.000 description 1
- 229960001334 Corticosteroids Drugs 0.000 description 1
- PXBRQCKWGAHEHS-UHFFFAOYSA-N Dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 1
- 229940093922 Gynecological Antibiotics Drugs 0.000 description 1
- ZFGMDIBRIDKWMY-PASTXAENSA-N Heparin Chemical compound CC(O)=N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O[C@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@@H](O[C@@H]3[C@@H](OC(O)[C@H](OS(O)(=O)=O)[C@H]3O)C(O)=O)O[C@@H]2O)CS(O)(=O)=O)[C@H](O)[C@H]1O ZFGMDIBRIDKWMY-PASTXAENSA-N 0.000 description 1
- 229960002897 Heparin Drugs 0.000 description 1
- 229960001361 Ipratropium Bromide Drugs 0.000 description 1
- NNPPMTNAJDCUHE-UHFFFAOYSA-N Isobutane Chemical compound CC(C)C NNPPMTNAJDCUHE-UHFFFAOYSA-N 0.000 description 1
- 229940039009 Isoproterenol Drugs 0.000 description 1
- 239000004341 Octafluorocyclobutane Substances 0.000 description 1
- 229960002969 Oleic Acid Drugs 0.000 description 1
- 229940026235 PROPYLENE GLYCOL MONOLAURATE Drugs 0.000 description 1
- 229920002048 Pluronic® L 92 Polymers 0.000 description 1
- IYMMESGOJVNCKV-SKDRFNHKSA-N Rimiterol Chemical compound C([C@@H]1[C@@H](O)C=2C=C(O)C(O)=CC=2)CCCN1 IYMMESGOJVNCKV-SKDRFNHKSA-N 0.000 description 1
- JNYAEWCLZODPBN-CTQIIAAMSA-N Sorbitan Chemical compound OCC(O)C1OCC(O)[C@@H]1O JNYAEWCLZODPBN-CTQIIAAMSA-N 0.000 description 1
- 229960000195 Terbutaline Drugs 0.000 description 1
- 229940024982 Topical Antifungal Antibiotics Drugs 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N Trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000001154 acute Effects 0.000 description 1
- UCTWMZQNUQWSLP-UHFFFAOYSA-N adrenaline Chemical compound CNCC(O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-UHFFFAOYSA-N 0.000 description 1
- 231100000494 adverse effect Toxicity 0.000 description 1
- 238000005054 agglomeration Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000000202 analgesic Effects 0.000 description 1
- 230000000954 anitussive Effects 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000003266 anti-allergic Effects 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 239000000043 antiallergic agent Substances 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 230000003078 antioxidant Effects 0.000 description 1
- 239000003434 antitussive agent Substances 0.000 description 1
- 230000003115 biocidal Effects 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
- 229910052799 carbon Inorganic materials 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 229960000265 cromoglicic acid Drugs 0.000 description 1
- 235000019404 dichlorodifluoromethane Nutrition 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
- LLRANSBEYQZKFY-UHFFFAOYSA-N dodecanoic acid;propane-1,2-diol Chemical compound CC(O)CO.CCCCCCCCCCCC(O)=O LLRANSBEYQZKFY-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229910001651 emery Inorganic materials 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 239000008079 hexane Substances 0.000 description 1
- 229940079866 intestinal antibiotics Drugs 0.000 description 1
- LHLMOSXCXGLMMN-VVQPYUEFSA-M ipratropium bromide Chemical compound [Br-].O([C@H]1C[C@H]2CC[C@@H](C1)[N@@+]2(C)C(C)C)C(=O)C(CO)C1=CC=CC=C1 LHLMOSXCXGLMMN-VVQPYUEFSA-M 0.000 description 1
- 239000001282 iso-butane Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000006011 modification reaction Methods 0.000 description 1
- 229940005935 ophthalmologic Antibiotics Drugs 0.000 description 1
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920001993 poloxamer 188 Polymers 0.000 description 1
- 229920002857 polybutadiene Polymers 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 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
- 229960001457 rimiterol Drugs 0.000 description 1
- 231100000486 side effect Toxicity 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 229940083878 topical for treatment of hemorrhoids and anal fissures Corticosteroids Drugs 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 239000005526 vasoconstrictor agent Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
-
- 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
- A61K9/10—Dispersions; Emulsions
- A61K9/12—Aerosols; Foams
- A61K9/124—Aerosols; Foams characterised by the propellant
-
- 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
- A61P11/08—Bronchodilators
-
- 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
- A61P11/14—Antitussive agents
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K3/00—Materials not provided for elsewhere
- C09K3/30—Materials not provided for elsewhere for aerosols
-
- Y10S514/826—
Description
NON-CHLOROFLUOROCARBON AEROSOL FORMULATIONS
INTRODUCTION TO THE INVENTION
The present invention is directed at aerosol formulations
which are substantially free of chloroiluorocarbons (CFC's). More
specifically, the present invention is directed at formulations
substantially free of CFC's and having particular utility in medicinal
applications, especially in metered dose pressurized inhalators (MDl's).
Metered dose inhalators have proven to be an effective
method for delivering medicaments orally and nasally. They have been
used extensively for delivering bronchodilating and steroidal
compounds to asthmatics and may also be useful for delivering other
compounds such as pentamidine and non-bronchodilator anti-
inflammatory drugs. The rapid onset of activity of compounds
administered in this manner and the absence of any significant side
effects have resulted in a large number of compounds being formulated
for administration via this route. Typically, the drug is delivered to the
patient by a propellant system generally comprising one or more
propellants which have the appropriate vapor pressure and which are
suitable for oral or nasal administration. The more preferred propellant
systems typically comprise propellant 11, propellant 12. propellant 114
or mixtures thereof. Often the vapor pressure of the propellant systems
is adjusted by admixing a liquid excipient with the propellant.
However, propellants 11, 12 and 114 belong to a class of
compounds known as chlorofluorocarbons, which have been linked to
the depletion of ozone in the atmosphere. It has been postulated that
ozone blocks certain harmful UV rays and that a decrease in the
atmospheric ozone content will result in an increase in the incidence of
skin cancer. In the 1970's certain steps were taken to reduce the CFC
emissions from aerosols. Other propellants, such as hydrocarbons,
were used, or the product was delivered in a different manner. Because
CFC usage in medicinal applications is relatively low i.e. less than 1% of
total CFC emissions, and because of the health benefits associated with
metered dose inhalators, steps were not taken at that time to restrict the
use of CFC propellants in metered dose inhalators.
However, continuing and more sophisticated ozone
measurements have indicated that the earlier restrictions in CFC usage
were insufficient and that additional, significant steps should be taken to
drastically reduce CFC emissions. Recently, recommendations have
been made that CFC production be virtually discontinued by the end of
this century. As a result, it may not be possible to continue to use CFC
propellants in the intermediate and long term. While some efforts have
been made to use non-pressurized metered dose inhalators, many of
these devices have not been completely successful. Many do not
deliver uniform doses, are mechanically complex, do not provide the
100-200 doses per unit of current aerosol containers, are difficult for
individuals to utilize, and are bulky and/or cumbersome for the patients
to use, particularly when they have an acute need for the medication.
As a result, there is a need for aerosol formulations which
are substantially free of CFC's. Non-CFC propellants systems must
meet several criteria for pressurized metered dose inhalators. They
must be non-toxic, stable and non—reactive with the medicament and the
other major components in the valve/actuator. One propellant which has
been found to be suitable is CF3-CH2F-CF3, also known as Freon 227,
HFA 227, HFC 227 or 1,1 ,1 ,2,3,3,3 heptafluoropropane. However,
certain physical properties, i.e., polarity and solubility, of HFC 227 differ
from those of commonly used CFC propellants. Commonly used
surfactants may be insoluble in HFA 227. Moreover, where the
medicament is to be delivered as a solution, the medicament may not be
readily soluble in this propellant. The polarity difference between HFC
227 and the previously used CFC propellants may result in a different
delivery of the medicament when HFC 227 replaces a CFC propellant.
The medicament may cream, settle or agglomerate in the non-CFC
propellant even though this did not occur in the CFO propellant.
The use of HFA 227 previously has been disclosed for use
in medicinal inhalators. European Patent Publication No. 0 384 371 is
directed at the combination of propellant 227 and propane, butane,
isobutane, Me2O and/or F2CHMe.
Reseereh Diselesure No. 30161, May, 1989 discloses that
non-CFC propellants, such as fluorohydrocarbons may be used in
pressurized medicaments delivered directly to the lungs, e.g.
bronchodilators.
Other publications have been directed at the use of other
fluorohydrocarbons, such as HFC 134a, for aerosol propellants.
European Patent Publication No. 0 372 777 is directed at medicinal
aerosol formulations incorporating HFC 134a and an adjuvant having a
higher polarity than the propellant. This publication lists several
possible adjuvants and surfactants for use in combination with the
propellant and the medicament.
_ International patent application No. WO 91/04011
discloses the combination of HFC 134a and a powdered medicament
pre-coated with a non-perfluorinated surfactant prior to dispersing the
powdered medicament in the propellant. Pages 6-7 of the publication
list suitablesurfactants for use with the propellant. A perfluorinated
adjuvant optionally could be added. However, the pre-coating of the
medicament may not be advantageous, since it adds an additional,
complex step to the manufacturing process,
U.S. Patent No. 4,174,295 discloses the combination of
HFC 134a_with various chlorofluorocarbons and optionally a saturated
hydrocarbon. U.S. Patent No. 2,885,427 discloses the use of HFC-134a
as an aerosol propellant. U.S. Patent No. 3,261,748 discloses the use
of HFC-134a for anesthesia. U.S. Patent Nos. 4,129,603, 4,311,863,
4,851,595 and European Publication No. 379,793 also disclose the use
of HFC-134a as an aerosol propellant.
However, the specific combinations noted above may not
provide the desired solubility, stability, low toxicity, exact dosage, correct
particle size (if suspension) and/or compatibility with commonly used
valves assemblies of metered dose inhalers.
Summary of the Invention
Accordingly, the present invention is directed at a non-toxic formulation
substantially free of CFC’s having improved stability and compatibility with the
medicament and which is relatively easily manufactured.
The present invention also is directed at formulations which may be
utilised in present aerosol filling equipment wfih only relatively minor
modifications and without pre—coating the medicament.
One embodiment of the present invention is directed at an inhalation
aerosol formulation comprising:
A.
B.
C.
an effective amount of mometasone furoate;
, 1, 1, 2, 3, 3, 3-heptafluoropropane;
an excipient to selected from the group consisting of:
propylene glycol diesters of media chain fatty acids;
triglyceride esters of medium chain fatty acids;
perfluorodimethylcyclobutane;
polyethylene glycol;
menthol;
lauroglycol;
diethylglycol monoethylether;
polyglycolized glycerides of medium chain fatty acids;
alcohols;
short chain fatty acids;
eucalyptus oil; and
combinations thereof; and
optionally, one of our component selected from one or more
of the following:
surfactants;
preservatives;
buffers;
antioxidants;
sweeteners; and
taste masking agents.
The surfactant is preferably selected from the group consisting of:
copolymers;
oleic acid;
sorbitan trioleate;
cetyl pyridinium chloride;
soya lecithin;
polyoxyethylene (20) sorbitan monolaurate;
polyoxyethylene (10) stearyl ether,
polyoxyethylene (2) oleyl ether, T
polyoxypropylene-polyoxyethylene-ethylene diarnine block
polyoxyethylene (20) sorbitan monostearate;
polyoxyethylene (20) sorbitan monoleate;
polyoxypropylene-polyoxyethyiene block copolymers;
castor oil ethoxylate; and combinations thereof.
The preferred liquid excipients are diethylene glycol monoethylether,
propyleneglycol diesters of medium chain fatty acids,
perfluorodimethylcyclobutane, polyethylene glycol, alcohols and triglyceride
esters of medium chain fatty acids.
The preferred surfactants are oleic acid, sorbitan trioleate, cetylpyridinium
chloride, polyoxyethylene (20) sorbitan trioleate, polyoxypropylene-
polycxyethyiene block copolymers; soya lecithin; and polyoxypropylene-
polyoxyethylene-ethylenediamine block copolymers; with oleic acid being
particularly preferred
The invention is of particular utility where the medicament
is albuterol, mometasone furoate or beclomethasone dipropionate, and
salts and clathrates thereof.
A useful formulation range comprises:
A. 1,1,1,2,3,3,3 heptafluoropropane 25 - 99.99 wt %
B. medicament 0.01 - 1 wt %
C. excipient 0 — 75 wt %
D. surfactant 0 - 3 wt %
The present invention also is directed at a method of
treating asthma in mammals comprising administering to a mammal in
need of such treatment an effective amount of aerosol formulation
comprising:
A. a medicament selected from the group comprising
albuterol, mometasone furoate, beclomethasone dipropionate, and salts
and clathrates thereof;
B. 1,1,1 ,2,3,3,3 heptafluoropropane; and
C. optionally an excipient selected from the group
consisting of:
propylene glycol diesters of medium chain
fatty acids;
triglyceride esters of medium chain fatty
acids;
perfluorodimethyIcyclobutane;
perfluorocyclobutane;
polyethylene glycol;
menthol;
lauroglycol;
diethyleneglycol monoethylether;
polyglycolized glycerides of medium chain
fatty acids;
alcohols;
short chain fatty acids;
eucalyptus oil; and combinations thereof.
A surfactant optionally is present. The surfactant preferably
is selected from the group consisting of:
oleic acid;
sorbitan trioleate;
cetyl pyridinium chloride;
soya lecithin;
polyoxyethylene (20) sorbitan monolaurate;
polyoxyethylene (10) stearyl ether;
polyoxyethylene (2) oleyl ether;
polyoxyethylene-polyoxypropylene-ethylene
diamine block copolymers;
polyoxyethylene (20) sorbitan monostearate;
polyoxypropylene-polyoxyethylene block
copolymers;
castor oil ethoxylate; and combinations
thereof.
DETAILED DESCRIPTION OF THE INVENTION
The formulations of the present invention all utilize
propellant 227 in combination with the medicament, optionally a liquid
excipient and optionally a surfactant.
The excipient facilitates the compatibility of the
medicament with the propellant and also lowers the discharge pressure
to an acceptable range i.e. about 2.76 ~ 5.52 x 105 newton/meter?
absolute (40 to 80 psia), preferably 3.45 - 4.83 x 105 newton/meter?
absolute (50 to 70 psia): The excipient chosen must be non-reactive
with the medicament, relatively non-toxic, and should have a vapor
pressure below about 3.45 x 105 newton/meter? absolute (50 psia). As
used hereinafter the term "medium chain fatty acids" refers to chains of
alkyl groups terminating in .a -COOH group and having 6-12 carbon
atoms, preferably 8-10 carbon atoms. The term "short chain fatty acids"
refers to chains of alkyl groups terminating in a -COOH group and
having 4-8 carbon atoms. The term "alcohol" includes C1-C3 alcohols,
such as methanol, ethanol and isopropanol. Among the preferred
excipients are:
propylene glycol diesters of medium chain fatty acids
available under the tradename Miglyol 840 (from Hiils America, Inc.
Piscataway, N.J.);
triglyceride esters of medium chain fatty acids available
under the tradename Miglyol 812 (from Hflls);
perfluorodimethylcyclobutane available under the
tradename Vertrel 245 (from E.l DuPont de Nemours and Co. Inc.
Wilmington, Delaware);
perfluorocyclobutane available under the tradename
octafluorocyclobutane (from PCR Gainsville, Florida);
polyethylene glycol available under the tradename PEG
400 (from BASF Parsippany, N.J.);
menthol (from Pluess-Stauffer international Stanford,
Connecticut);
propylene glycol monolaurate available under the
tradename lauroglycol (from Gattefossé Elmsford, N.Y.);
diethylene glycol monoethylether available under the
tradename Transcutol (from Gattefossé);
polyglycolized glyceride of medium chain fatty acids
available under the tradename Labrafac Hydro WL 1219 (from
Gattefossé);
alcohols, such as ethanol, methanol and isopropanol;
eucalyptus oil available (from Pluess-Stauffer '
international); and mixtures thereof.
A surfactant optionally may be added to lower the surface
and interfacial tension between the medicament and the propellant.
Where the medicament, propellant and excipient are to fonn a
suspension, a surfactant may or may not be required. Where the
medicament, propellant and excipient are to form a solution, a surfactant
may or may not be necessary, depending in part, on the solubility of the
L particular medicament and excipient. The surfactant may be any
suitable, non-toxic compound which is non-reactive with the
medicament and which substantially reduces the surface tension
between the medicament, the excipient and the propellant and/or acts
as a valve lubricant. Among the preferred surfactants are:
oleic acid available under the tradename oleic acid
NF6321 (from Henkel Corp. Emery Group, Cincinnati, Ohio);
cetylpyridinium chloride (from Arrow Chemical, Inc.
Westwood, N.J.);
soya lecithin available under the tradename Epikuron 200
(from Lucas Meyer Decatur, Illinois);
polyoxyethylene(20) sorbitan monolaurate available under
the tradename Tween 20 (from ICI Specialty Chemicals, Wilmington,
Delaware); '
polyoxyethylene(20) sorbitan monostearate available
under the tradename Tween 60 (from lCl); .
po|yoxyethylene(20) sorbitan monooleate available under
the tradename Tween 80 (from ICI);
polyoxyethylene (10) stearyl ether available under the
tradename Brij 76 (from ICI);
polyoxyethylene (2) oleyl ether available under the
tradename Brij 92 (from lCl);
polyoxyethylene-polyoxypropylene-ethylenediamine block
copolymer available under the tradename Tetronic 150 R1 (from BASF);
polyoxypropylene-polyoxyethylene block copolymers
available under the tradenames Pluronic L—92, Pluronic L-121 and
Pluronic F 68 (from BASF);
castor oil ethoxylate available under the tradename
Alkasurf CO-40 (from Rhone-Poulenc Mississauga Ontario,Canada);
and mixtures thereof. _
The medicaments of the present invention may include any
pharmaceutically active compounds which are to be delivered by oral
inhalation or nasally. Typical classes of compounds include
bronchodilators, anti-inflammatory compounds, antihistamines,
antiallergics, analgesics, antitussives, anti-angina! medications,
steroids, corticosteroids, vasoconstrictors and antibiotics. Specific
compounds within these classes of compounds are albuterol,
mometasone furoate, beclomethasone dipropionate, isoproterenol,
heparin, terbutaline, rimiterol, perbuterol, disodium cromoglycate,
isoprenaline, adrenaline, pentamidine and ipratropium bromide. These
compounds may be utilized either as the free base, as a salt, or as a
clathrate, depending upon the stability and solubility of the active
compound in the specific formulation. When clathrates are utilized, P-11
and hexane clathrates are particularly preferred.
Where the active compound forms a suspension, the
particle size should be relatively uniform, with substantially all the
particles preferably ranging between about 0.1-25 microns, preferably
0.5-10 microns, more preferably 1-5 microns. Particles larger than 25
microns may be held up in the oropharyngeal cavity, while particles
smaller than about 0.5 micron preferably are not utilized, since they
would be more likely to be exhaled and, therefore, not reach the lungs of
the patient.
The formulations of the present invention may be filled into
the aerosol containers using conventional filling equipment. Since
propellant 227 may not be compatible with all elastomeric compounds
currently utilized in present aerosol valve assemblies, it may be
necessary togsubstitute other materials, such as white buna rubber, or to
utilize excipients and optionally surfactants which mitigate the adverse
effects of propellant 227 on the valve components.
To assure uniform dispersion of the active ingredient, the
formulations typically will include the following components:
Preferred Moe; Preferreg
Ear19.e_(v_vt_‘3/21 Et_a_r19.e_lm:’zal Bang9_lm.‘Zel
Medicament 0.01 - 1 0.03 - 0.7 0.05 - o.5
Propellant 25 - 99.99 50 - 99.97 50 - 99.95
Excipient(s) o - 75 o — so '0 - 50
Surfactant(s), O - 3 0 - 2 0 - 1
Depending on the particular application, the container may
be charged with a predetermined quantity of formulation for single or
multiple dosing. Typically, -the container is sized for multiple-dosing,
and, therefore, it is very important that the formulation delivered is
substantially uniform for each dosing. For example, where the
formulation is for bronchodilation, the container typically is charged with
a sufficient quantity of the formulation for 200 charges.
Suitable suspensions may be screened in part by
observing several physical properties of the formulation, i.e. the rate of
particle agglomeration, the size of the agglomerates and the rate of
particulate creaming/settling and comparing these to an acceptable
standard. Suitable solutions may be screened by observing the
solubility of the medicament over the entire recommended storage
temperature range.
Suspensions of the present invention preferably may be
prepared by either the pressure filling or cold filling procedures well-
known in the art.
For metered dose inhalators, suspensions may be
particularly preferred for efficacy and stability considerations.
Those skilled in the art may choose to add one or more
preservative, buffer, antioxidant, sweetener and/or flavors or other taste
masking agents depending upon the characteristics of the formulation.
Examples I - XXXIII below further describe the present
invention. For several of the examples, alternative formulations denoted
as A and B are provided.
Qomponent _V\_lt_%g
EXAMPLE I
A B
Albuterol 0.5 0.1
Mlglyol 812 10.0 1.0
HFC-227 89.5 98.9
EXAMPLE II
Albuterol 0.1
Transcutol 25.0
HFC-227 74.9
Albuterol
Miglyol 840 I
HFC-227
Albuterol
PEG 400
HFC-227
Albuterol
Menthoi
HFC 227
Albuterol
Lauroglycol
HFC 227
Albuterol
Vertrel 245
HFC 227
EXAMPLE III
A B
0.5 0.1
.0 1.0
89.5 98.9
EXAMPLE IV
0.1
1.0
98.9
EXAMPLE V
98.9
EXAMPLE VI
A B
0.1 0.1
0.1 0.5
99.8 99.4
EXAMPLE VII
A B
0.1 0.5
.0 49.6
89.9 49.9
' .'_ '
. Aibuterol
Labrafac Hydro 9111. 1219
HFC 227
Albuferd! A‘ , -
Petffuorocyclobtjtanwe
HFC 227 .
Mometaisone Fiuoate
mayo: 812_
HFC227
Tetronic 150 31
», Mometasorpe Furoafe j
Miglydi £112: _
HFC»-227: , -A
Mometasqhe-Fumate '
V . _Mig1yo1_81'2
'9” A°“‘—.'.' , . . .
Tefrohic "150 R1
HFC-227 j
EXAMPLEVIII 4
11.1
0.5
99.4
EXAMELEIX’
A B
0.1 ' '~o}5
1o.o 49.6
89.9 ' {£9.97
EXAMPLE x .
_A 13 1
0-1. 0,-1
0.1 9.1" ~
1.0 _ 10.0
98.81 J 39.3‘
E)(AMPLE x1
1 o}.1v
on .
9.;8
_ 90 .
E)
.0;.1 _:
9
0.005
0.01"
.835’
_ Oleic Acid
Mometasone Furbate -
_ Miglyol 812
HFC 227
Dipiqpibnaie. ~ 0,1
Mgtyou 8'12 " -
-IHFC 22.7.
' ‘_Bec!6'methaSone Dipiopibhate j_ 3 1’ __ -1 _0.1
PEG400
, HFC 227
, EXAMPLE XIII 1
A, 0,001
0.1 .
1.0
.8
EXAMPLE XIV
u. 1.0’
‘ ‘ “ , 93:9
EXAMPLE XV
_ 1L0
. i_98;9
.01
0.1
.0
‘ 89.8
=o.1-"
.0
¢ 39.9
-0.1
V 010.0 T
T HFC 227 ‘
EXAMPLE XVI
" j Beclornethasone Dipropionate . 0.1
Ethanol ~ _ 5 _
94.9.
While the examples above hétve been directed at albuterot,
albuterol sulfate, mometasone furoate, bectomethasone dipropionate ‘
artdbectomethasone qipropionate clathrates, it iscorttemplated that
- other orally or nasally administered medicamentsoould be utilized. 2
it is contemplated that excipients and surfactants other that:
those exemplified maybe utiiized; , " . _ .
The descriptionsot the foregoing ernboriments of the
_ invention been presented for the purpose of and
1 0 ,
;deserrption,. They arenot intended to be exhaustive orto limit the
invention to the precise tonne ésciosed,-and ohyiousty many ’
and vafiafions are possible in fight of the ebove teaohing.
The embodirnents were chosen described in order to best
~ the pnneiptes ot the invention and its practical apoieattonto thereby .. . . _
others erdued in‘-the ertto besrutiti'zet'he invention in various
embodiments with various as.are suited to. the
.parhcu' "Iar use cortternptateo} 1 his ’intended': that the soope_ .‘ otthef
invention be defined by the daimseppehded hereto. _ .
Claims (3)
- CLAIMS: 1. An inhalation aerosol formulation comprising: A. B. C". D. an effective amount ofmometasone furoate; 1 ,1,1 ,2,3,3,3—heptafluoropropane; an excipient selected from the group consisting of: propylene glycol diesters of medium chain fatty acids; triglyceride esters of medium chain fatty acids; perfiuorodimethylcyclobutane; polyethylene glycol; menthol; 1 lauroglyool; diethylglyool monoethylether, I polyglycofized glycerides of medium chain fatty acids; alcohols; short chain fatty acids; eucalyptus oil; and combinations thereof, and A optionally, one or more components selected from one or more of the following: surfactants; preservatives; buffers; antioxidants; sweeteners; and taste masking agents.
- 2. A fonnulation according to anycpreceding claim, wherein themornetasone furoate is a powder having a mean particle size of1 to 5 microns.
- 3. A formulation according to any preceding claim containing: . Comm ‘went W§rg' fit Percent Mometasone furoate 0.014 2599.94 1,1 ,1,2,3,3,3-heptafluoropropanee 0.0575 O-3 Excipient Surfactant 4. A formulation according to any preceding claim containing: Commnent Weight Percent Mometasone furoate 0.03—O.7 ' 1 ,1 ,1 ,2,3,3,3i-heptatluoropropané 50'—99.87 Excipient 0.1-50 ' Surfactant 0-2 5. A formulaticn according to any preceding claim containing: Component Weight Percent Mometasone furoate o.oso.5 1,1,1,2,3,3,3~heptafluoropropane 50-98.95 Excipient A 1-50 Surfactant 0-1 6. A formulation according to any preceding claim for the treatment of asthma. 7. An aerosol dispersion of mometasone furoate and 1,1,1,2,3,3,3- heptafluoropmpane for the treatment of asthma further comprising anexcipient selected from the group consisting of propylene glycol diesters of medium chain fatty acids; tn‘glyceride.esters'of medium chain fatty acids; perfluorodimethylcyciobutane; potyethyiene glycol; menthol; lauroglycol; diethylglycol monoethyiethen polyglycolized glycefides of medium chain fatty acids; alcohols; ' A short chain fatty acids; eucalyptus ‘c‘i1"; and combinations thereof. ,8. 18 An aerosol dispersion of mometasone furoate and 1 ,1,1,2,3,3,3- heptafluoropropane for the treatment of asthma further comprising A an excipient selected from the group consisting of. propylene glycol diesters of medium chain fatty acids; triglyceride esters of medium chain fatty acids; perfluorodimethylcyclobutane; polyethylene glycol; menthol; lauroglyool; dietliylglyool monoethylether; polyglycolized glycerides of medium chain fatty acids; alcohols; I short chain fatty acids; eucalyptus oii; and combinations thereof, further comprising a surfactant selected from the group oonsisting of. oleic acid; sorbitan trioleate; oetyl pyridinium chloride; soya lecithin; ‘ polyoxyethylene (20) sorbitan monolaurate; polyoxyethylene (20) sorbitan monostearate; poiyoxyethylene (20) sorbitan monooleate; polyoxypropflylene-polyoxyethylene block oopolymers; castor oil ethoxyiate; and 1 combinations thereof. Use of mometasone fumate in association with 1,1,1 ,-2,3,13,3- hepfatiuoropiopane and an excipient selected from the group oonsisfing of: propylene glycol diesteis of medium chain ‘fatty acids; triglyceride esters of medium chain fatty acids; perfluorodimethylcyclobutane; polyefliyiefle glycol; rfientfrbl; lauioglycol; diethylglycol rfibfidéthyiétlieit polygiycoliiied giycérides i 35 11. 12. 19 of meiiium chain fatty acids; alcohols; short chain fatty acids; eucalyptus oil; and combinations thereof; in the manufacture of an inhalation aerosol medicament for treating asthma. Anacros'olfonnulationconsisting_of:_ , . i % A. anetTectivcamountofamedicamémtsclectedfi’oma1butcrolangi§aIts , thereof, dipmpionatcandclathrates thewof, wbgrcinthc >. ' ‘ mcdicammtisapowdcthavinganieanparflcIcsizeof0.5-10ipicrons;and _V . B. l,l,l2,33, mfl ’ ' C. o;nionafly,oncor1riomoonipona1xiselectcdfro:noneormora:¢)fthcA . following: . '— - l i preservatives; sw%;an<1 tasticmaskingagcntgand D. mncornzorcexcipiatssdcctcdfiomflxefonowingz propylcncglyooldicstetVofaC.»C,,fanyacid; i triglycefide csserotao.-,c,,rauyacid; Polycfllylcncglyool; menthol; dicthylcncglyoolmonocthylcthct; ’ A vP°l3lS1Y°°1iz°d8lY°“.id¢°f_3CrCnf3“Y89id; . " alcohols: ‘ ' r élcalyptllsoil; . C.€.fattyacid-6: andyoombinafionsthereof. AfoInnlétion_aowrdingt0Clahn10contg;ining0,01fo1p¢m¢n;byw§igm . medicament. .. ' l ' 1 ‘ Aformulation acoordingtoClaim lloontaining 0Q03to0.7 pcrceml>)ty(etgl1t » A fommlation according to Claim 12 containing 0.05 to 0.5 percent by weight‘. 35 15. I7. 20 A formmafion awarding to any of claims 10 to 13 wheusin the médicamcntjs a powder having a mean particle size of 1-5 microns. A formulation aoéording to any of Claims 10 to 14, comprising an nxcipicm scxencea fmmpropyjene glycol dicstcr ofa Cpgu fatty acid and a lliglyceride cstqpfa Cc Cn fatty acid. A fotmulation accordingizoanyof Claims 10 t'ol5 for thetrwtmcnt ofasthma. Use ofalbuterol or aéalt thcreofin 1,1,1,2,3,3,3,_. ncpunnoiopmpaneandanexcipiantinmemamracmxeorasmrncmu-tree‘ _ medxcamcnt’ nwhcremsaidmedicamanisapowdahavingamganjamficksizcofoj-lflhtictmn andwhcrcinthecxcipiantisselccwdfmmz pwpnenczryeowicsseroracrcnrauyacsa; triglyceride cstcrofaC‘_-C-ufattyacid; Polyeihylweélywl; menthol; lanmslyeol; . polyglyoolizedglyoeridcb'fa?C;-C.,fattyacid; J wcalyptusoil; C4-Csf811Ya°id33 . andcombinationsthcreof; T Useofbeclonmcthasone dipropionatcoraclathmcthcreofin ’ 1,1,1,2,3,3,_3, hcptaflnotopropanc and an exnipinm in tbemanufauure ofa ' . - surfactant~freé medicament rofnrax andlor to apaticnt nomasmma,wne:einsaidmeascamentisapoygaanavingamcnnpn;nn1¢_s:zcor 0.5-10 microns and wherein the cxcipicnt is selected from: _« ’ propylene glycol diestct on 0.42,, fatty acid; ' tliglyceride : ester of a C,-Cafatty acid; pctfluorodimethylcyclobuinnc;. T perfluorocyclobutanc; ‘ Polvcthylwc glycol; menthol; lauroglycol; dicthylenc glycol monoethylcthcr; . - po1yglyoo1izedglyceridcofa.C,.-C,, acid; ' ‘ A alcohols‘ . — ' » eucalyptusoil; CFC: Wt)’ 59553; and combinations thereof. 19- Uscofalisutcmlotasahflrawfinthcmamfaéfitfeiofasurfaw-fiecaciogol. 20. vpham1aoenficalcmhposifion,saidconq:osiflonomnprisingl,l,l,2,3,3,3~ ' . hegguflumopropmncaspropdhxnforflwueammtofasdnmbymalmndlornaéél’ adnfinkuaflomwhcrcinsaidanmuolorsahthqeofisapawdethayingamcan‘ par6cIesizcof0.5-lomiumnandvbhadnsaidoomposifimdsocomprisesafi propylene g1ycolvdi<'sh=r.0f 3' fatty triglyceride _ pcrfluorodinxcfltylcyclobutanc; pcrfluorocyclobutane; polyethyleneglyool; menthol; diethylcneglycolmonocfllylefihcrz polyglyoolizedglyccridcofac‘-C,,fittyacid; alcohols; T .- Cucalypwsoil; ‘ _ C4-C,fattyacids; T w Use ofbcdomahasomdfpmgfomtemadamfimdmioofmthemamfacuéreofé 1,1.1,2,3,3,3 hcptafluoropropanc as propellant forthctrcauixent ofasthma by oial andlorTnasaladminisuafion,whcreinsaidbeclmndhésonediptopfionamora " clathmtethereofisapowderhavingameanpatficlcsiicofoj-Iomicronsand ' wherein said composition alsooomptises an cxcipiexit selected from: - propylene glycol dicstcr of a C¢C,2 fatty acid; triglyceride cm; ofa cccn ‘fatty acid; pcrtluorodimcflxylcyclobmanc; Pcffiuorocydobmane: . Polyethylene glycol; menthol; lanrosiyéolz . ' pozygyoolized glycbrides of a.c¢c,, my acid; alcohols; 4 b ’ - cncalypuis oil; Ca-Cs fatty acids; and combinations thereof.
Applications Claiming Priority (2)
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USUNITEDSTATESOFAMERICA10/06/19910 | |||
US71279191A | 1991-06-10 | 1991-06-10 |
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IE83747B1 true IE83747B1 (en) | |
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IE184792A IE921847A1 (en) | 1991-06-10 | 1992-07-01 | Non-chlorofluorocarbon aerosol formulations |
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US (1) | US5474759A (en) |
EP (5) | EP0588897B1 (en) |
JP (1) | JP3323199B2 (en) |
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AT (4) | ATE203901T1 (en) |
AU (1) | AU2017592A (en) |
CA (1) | CA2111002C (en) |
CZ (1) | CZ271493A3 (en) |
DE (4) | DE69233150T2 (en) |
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FI (1) | FI935464A0 (en) |
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-
1992
- 1992-06-08 SK SK1404-93A patent/SK140493A3/en unknown
- 1992-06-08 DE DE69233150T patent/DE69233150T2/en not_active Expired - Lifetime
- 1992-06-08 AT AT95102113T patent/ATE203901T1/en active
- 1992-06-08 EP EP92912490A patent/EP0588897B1/en not_active Revoked
- 1992-06-08 NZ NZ243061A patent/NZ243061A/en unknown
- 1992-06-08 PT PT95102113T patent/PT656206E/en unknown
- 1992-06-08 DE DE69208660T patent/DE69208660T2/en not_active Revoked
- 1992-06-08 HU HU9303517A patent/HUT67449A/en unknown
- 1992-06-08 YU YU59092A patent/YU59092A/en unknown
- 1992-06-08 CZ CS932714A patent/CZ271493A3/en unknown
- 1992-06-08 AT AT92912490T patent/ATE134509T1/en not_active IP Right Cessation
- 1992-06-08 DE DE69231994T patent/DE69231994T3/en not_active Expired - Lifetime
- 1992-06-08 DK DK95102113T patent/DK0656206T3/en active
- 1992-06-08 EP EP92305252A patent/EP0518600A1/en active Pending
- 1992-06-08 PT PT95102114T patent/PT656207E/en unknown
- 1992-06-08 WO PCT/US1992/004619 patent/WO1992022288A1/en not_active Application Discontinuation
- 1992-06-08 AT AT00122297T patent/ATE246497T1/en not_active IP Right Cessation
- 1992-06-08 ES ES95102113T patent/ES2158910T3/en not_active Expired - Lifetime
- 1992-06-08 DK DK92912490.7T patent/DK0588897T3/en active
- 1992-06-08 EP EP00122297A patent/EP1092430B1/en not_active Expired - Lifetime
- 1992-06-08 ZA ZA924164A patent/ZA924164B/en unknown
- 1992-06-08 ES ES00122297T patent/ES2200771T3/en not_active Expired - Lifetime
- 1992-06-08 IL IL102131A patent/IL102131A0/en unknown
- 1992-06-08 EP EP95102114A patent/EP0656207B2/en not_active Expired - Lifetime
- 1992-06-08 DE DE69231992T patent/DE69231992T2/en not_active Expired - Lifetime
- 1992-06-08 EP EP95102113A patent/EP0656206B1/en not_active Expired - Lifetime
- 1992-06-08 ES ES95102114T patent/ES2158911T5/en not_active Expired - Lifetime
- 1992-06-08 DK DK95102114T patent/DK0656207T4/en active
- 1992-06-08 US US08/157,182 patent/US5474759A/en not_active Expired - Lifetime
- 1992-06-08 AU AU20175/92A patent/AU2017592A/en not_active Abandoned
- 1992-06-08 AT AT95102114T patent/ATE203902T1/en active
- 1992-06-08 ES ES92912490T patent/ES2084360T3/en not_active Expired - Lifetime
- 1992-06-08 CA CA002111002A patent/CA2111002C/en not_active Expired - Lifetime
- 1992-06-08 JP JP50090793A patent/JP3323199B2/en not_active Expired - Lifetime
- 1992-06-09 MX MX9202750A patent/MX9202750A/en unknown
- 1992-06-09 CN CN92104505A patent/CN1067578A/en active Pending
- 1992-07-01 IE IE184792A patent/IE921847A1/en not_active IP Right Cessation
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1993
- 1993-12-07 FI FI935464A patent/FI935464A0/en not_active Application Discontinuation
- 1993-12-09 NO NO934500D patent/NO934500D0/en unknown
- 1993-12-09 OA OA60447A patent/OA09868A/en unknown
- 1993-12-09 NO NO934500A patent/NO934500L/en unknown
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1996
- 1996-03-20 GR GR960400774T patent/GR3019374T3/en unknown
- 1996-10-03 HK HK185596A patent/HK185596A/en not_active IP Right Cessation
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2001
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- 2001-10-30 GR GR20010401916T patent/GR3037044T3/en unknown
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