US3014844A - Self-propelling powder dispensing compositions - Google Patents
Self-propelling powder dispensing compositions Download PDFInfo
- Publication number
- US3014844A US3014844A US706908A US70690858A US3014844A US 3014844 A US3014844 A US 3014844A US 706908 A US706908 A US 706908A US 70690858 A US70690858 A US 70690858A US 3014844 A US3014844 A US 3014844A
- Authority
- US
- United States
- Prior art keywords
- powder
- propellant
- freon
- crystalline
- column
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 239000000843 powder Substances 0.000 title claims description 104
- 239000000203 mixture Substances 0.000 title claims description 97
- 239000003380 propellant Substances 0.000 claims description 72
- 239000002245 particle Substances 0.000 claims description 45
- 239000004094 surface-active agent Substances 0.000 claims description 37
- 239000000443 aerosol Substances 0.000 claims description 29
- 239000000126 substance Substances 0.000 claims description 19
- 239000007788 liquid Substances 0.000 claims description 12
- PRXRUNOAOLTIEF-ADSICKODSA-N Sorbitan trioleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCC\C=C/CCCCCCCC)[C@H]1OC[C@H](O)[C@H]1OC(=O)CCCCCCC\C=C/CCCCCCCC PRXRUNOAOLTIEF-ADSICKODSA-N 0.000 description 49
- 239000007787 solid Substances 0.000 description 35
- 239000004147 Sorbitan trioleate Substances 0.000 description 24
- 235000019337 sorbitan trioleate Nutrition 0.000 description 24
- 229960000391 sorbitan trioleate Drugs 0.000 description 24
- 239000003814 drug Substances 0.000 description 20
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 19
- 235000019404 dichlorodifluoromethane Nutrition 0.000 description 19
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 19
- 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 17
- -1 adrnochrome Proteins 0.000 description 15
- 239000000725 suspension Substances 0.000 description 14
- 229960003733 phenylephrine hydrochloride Drugs 0.000 description 13
- OCYSGIYOVXAGKQ-FVGYRXGTSA-N phenylephrine hydrochloride Chemical compound [H+].[Cl-].CNC[C@H](O)C1=CC=CC(O)=C1 OCYSGIYOVXAGKQ-FVGYRXGTSA-N 0.000 description 13
- 230000005484 gravity Effects 0.000 description 11
- PGBHMTALBVVCIT-VCIWKGPPSA-N framycetin Chemical compound N[C@@H]1[C@@H](O)[C@H](O)[C@H](CN)O[C@@H]1O[C@H]1[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](N)C[C@@H](N)[C@@H]2O)O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CN)O2)N)O[C@@H]1CO PGBHMTALBVVCIT-VCIWKGPPSA-N 0.000 description 10
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 10
- 229940053050 neomycin sulfate Drugs 0.000 description 10
- 239000004338 Dichlorodifluoromethane Substances 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- ALEXXDVDDISNDU-JZYPGELDSA-N cortisol 21-acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)C[C@@H]2O ALEXXDVDDISNDU-JZYPGELDSA-N 0.000 description 9
- 229960001067 hydrocortisone acetate Drugs 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 8
- 229910052938 sodium sulfate Inorganic materials 0.000 description 8
- 235000011152 sodium sulphate Nutrition 0.000 description 8
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical class OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 7
- 239000002537 cosmetic Substances 0.000 description 7
- 229940087091 dichlorotetrafluoroethane Drugs 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 6
- 239000000470 constituent Substances 0.000 description 6
- 238000012937 correction Methods 0.000 description 6
- RMRCNWBMXRMIRW-BYFNXCQMSA-M cyanocobalamin Chemical compound N#C[Co+]N([C@]1([H])[C@H](CC(N)=O)[C@]\2(CCC(=O)NC[C@H](C)OP(O)(=O)OC3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)C)C/2=C(C)\C([C@H](C/2(C)C)CCC(N)=O)=N\C\2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O RMRCNWBMXRMIRW-BYFNXCQMSA-M 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- 239000008101 lactose Substances 0.000 description 6
- 231100000252 nontoxic Toxicity 0.000 description 6
- 230000003000 nontoxic effect Effects 0.000 description 6
- 101800000414 Corticotropin Proteins 0.000 description 5
- 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 5
- 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 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- DYWNLSQWJMTVGJ-KUSKTZOESA-N Phenylpropanolamine hydrochloride Chemical compound Cl.C[C@H](N)[C@H](O)C1=CC=CC=C1 DYWNLSQWJMTVGJ-KUSKTZOESA-N 0.000 description 5
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 5
- IDLFZVILOHSSID-OVLDLUHVSA-N corticotropin Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)NC(=O)[C@@H](N)CO)C1=CC=C(O)C=C1 IDLFZVILOHSSID-OVLDLUHVSA-N 0.000 description 5
- 229960000258 corticotropin Drugs 0.000 description 5
- 229960000890 hydrocortisone Drugs 0.000 description 5
- 238000002664 inhalation therapy Methods 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 5
- 229960002305 phenylpropanolamine hydrochloride Drugs 0.000 description 5
- 239000000600 sorbitol Substances 0.000 description 5
- CUNWUEBNSZSNRX-RKGWDQTMSA-N (2r,3r,4r,5s)-hexane-1,2,3,4,5,6-hexol;(z)-octadec-9-enoic acid Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.CCCCCCCC\C=C/CCCCCCCC(O)=O.CCCCCCCC\C=C/CCCCCCCC(O)=O.CCCCCCCC\C=C/CCCCCCCC(O)=O CUNWUEBNSZSNRX-RKGWDQTMSA-N 0.000 description 4
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 4
- 229930182837 (R)-adrenaline Natural products 0.000 description 4
- AJDIZQLSFPQPEY-UHFFFAOYSA-N 1,1,2-Trichlorotrifluoroethane Chemical compound FC(F)(Cl)C(F)(Cl)Cl AJDIZQLSFPQPEY-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 238000005054 agglomeration Methods 0.000 description 4
- 230000002776 aggregation Effects 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 229960005139 epinephrine Drugs 0.000 description 4
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 4
- 239000000314 lubricant Substances 0.000 description 4
- 239000002798 polar solvent Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 150000003839 salts Chemical group 0.000 description 4
- JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 description 3
- YLXIPWWIOISBDD-NDAAPVSOSA-N (2r,3r)-2,3-dihydroxybutanedioic acid;4-[(1r)-1-hydroxy-2-(methylamino)ethyl]benzene-1,2-diol Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.CNC[C@H](O)C1=CC=C(O)C(O)=C1 YLXIPWWIOISBDD-NDAAPVSOSA-N 0.000 description 3
- XNVYXHPPYWIPKX-UHFFFAOYSA-N 2,2,5,7-tetramethyl-1-oxo-3h-indene-4-carbonyl chloride Chemical compound CC1=CC(C)=C(C(Cl)=O)C2=C1C(=O)C(C)(C)C2 XNVYXHPPYWIPKX-UHFFFAOYSA-N 0.000 description 3
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 102000051325 Glucagon Human genes 0.000 description 3
- 108060003199 Glucagon Proteins 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- NWGKJDSIEKMTRX-AAZCQSIUSA-N Sorbitan monooleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-AAZCQSIUSA-N 0.000 description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 3
- 150000001335 aliphatic alkanes Chemical class 0.000 description 3
- 239000001273 butane Substances 0.000 description 3
- 239000001110 calcium chloride Substances 0.000 description 3
- 229910001628 calcium chloride Inorganic materials 0.000 description 3
- 239000006184 cosolvent Substances 0.000 description 3
- 229960002104 cyanocobalamin Drugs 0.000 description 3
- 235000000639 cyanocobalamin Nutrition 0.000 description 3
- 239000011666 cyanocobalamin Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 229960003157 epinephrine bitartrate Drugs 0.000 description 3
- MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 description 3
- 229960004666 glucagon Drugs 0.000 description 3
- 229940088597 hormone Drugs 0.000 description 3
- 239000005556 hormone Substances 0.000 description 3
- 239000007791 liquid phase Substances 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 229960001490 methapyrilene hydrochloride Drugs 0.000 description 3
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 3
- 229960001802 phenylephrine Drugs 0.000 description 3
- SONNWYBIRXJNDC-VIFPVBQESA-N phenylephrine Chemical compound CNC[C@H](O)C1=CC=CC(O)=C1 SONNWYBIRXJNDC-VIFPVBQESA-N 0.000 description 3
- PWZUUYSISTUNDW-VAFBSOEGSA-N quinestrol Chemical compound C([C@@H]1[C@@H](C2=CC=3)CC[C@]4([C@H]1CC[C@@]4(O)C#C)C)CC2=CC=3OC1CCCC1 PWZUUYSISTUNDW-VAFBSOEGSA-N 0.000 description 3
- 239000011343 solid material Substances 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 229940029284 trichlorofluoromethane Drugs 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 description 2
- AKNNEGZIBPJZJG-MSOLQXFVSA-N (-)-noscapine Chemical compound CN1CCC2=CC=3OCOC=3C(OC)=C2[C@@H]1[C@@H]1C2=CC=C(OC)C(OC)=C2C(=O)O1 AKNNEGZIBPJZJG-MSOLQXFVSA-N 0.000 description 2
- QYAPHLRPFNSDNH-MRFRVZCGSA-N (4s,4as,5as,6s,12ar)-7-chloro-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4,4a,5,5a-tetrahydrotetracene-2-carboxamide;hydrochloride Chemical compound Cl.C1=CC(Cl)=C2[C@](O)(C)[C@H]3C[C@H]4[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]4(O)C(=O)C3=C(O)C2=C1O QYAPHLRPFNSDNH-MRFRVZCGSA-N 0.000 description 2
- IAKHMKGGTNLKSZ-INIZCTEOSA-N (S)-colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 description 2
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 2
- ZOLBALGTFCCTJF-UHFFFAOYSA-N 4-[1-hydroxy-2-(propan-2-ylamino)ethyl]benzene-1,2-diol;sulfuric acid Chemical compound OS(O)(=O)=O.CC(C)NCC(O)C1=CC=C(O)C(O)=C1.CC(C)NCC(O)C1=CC=C(O)C(O)=C1 ZOLBALGTFCCTJF-UHFFFAOYSA-N 0.000 description 2
- SDEBYHVDMCQKNZ-UHFFFAOYSA-N 4-methoxy-6-piperazin-1-ylpyrimidine;hydrochloride Chemical compound Cl.C1=NC(OC)=CC(N2CCNCC2)=N1 SDEBYHVDMCQKNZ-UHFFFAOYSA-N 0.000 description 2
- RPHLQSHHTJORHI-UHFFFAOYSA-N Adrenochrome Chemical compound O=C1C(=O)C=C2N(C)CC(O)C2=C1 RPHLQSHHTJORHI-UHFFFAOYSA-N 0.000 description 2
- 239000000055 Corticotropin-Releasing Hormone Substances 0.000 description 2
- IROWCYIEJAOFOW-UHFFFAOYSA-N DL-Isoprenaline hydrochloride Chemical compound Cl.CC(C)NCC(O)C1=CC=C(O)C(O)=C1 IROWCYIEJAOFOW-UHFFFAOYSA-N 0.000 description 2
- 102000004877 Insulin Human genes 0.000 description 2
- 108090001061 Insulin Proteins 0.000 description 2
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- 102000004142 Trypsin Human genes 0.000 description 2
- 108090000631 Trypsin Proteins 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- AKNNEGZIBPJZJG-UHFFFAOYSA-N alpha-noscapine Natural products CN1CCC2=CC=3OCOC=3C(OC)=C2C1C1C2=CC=C(OC)C(OC)=C2C(=O)O1 AKNNEGZIBPJZJG-UHFFFAOYSA-N 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 description 2
- 239000002274 desiccant Substances 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 230000014509 gene expression Effects 0.000 description 2
- 239000010439 graphite Substances 0.000 description 2
- 229910002804 graphite Inorganic materials 0.000 description 2
- WVLOADHCBXTIJK-YNHQPCIGSA-N hydromorphone Chemical compound O([C@H]1C(CC[C@H]23)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O WVLOADHCBXTIJK-YNHQPCIGSA-N 0.000 description 2
- 229940125396 insulin Drugs 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- YOBAEOGBNPPUQV-UHFFFAOYSA-N iron;trihydrate Chemical compound O.O.O.[Fe].[Fe] YOBAEOGBNPPUQV-UHFFFAOYSA-N 0.000 description 2
- 229940039009 isoproterenol Drugs 0.000 description 2
- 229940018435 isoproterenol sulfate Drugs 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 2
- PLPRGLOFPNJOTN-UHFFFAOYSA-N narcotine Natural products COc1ccc2C(OC(=O)c2c1OC)C3Cc4c(CN3C)cc5OCOc5c4OC PLPRGLOFPNJOTN-UHFFFAOYSA-N 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- 235000021313 oleic acid Nutrition 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- 235000019271 petrolatum Nutrition 0.000 description 2
- 238000005498 polishing Methods 0.000 description 2
- 229920000136 polysorbate Polymers 0.000 description 2
- 239000012254 powdered material Substances 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000001593 sorbitan monooleate Substances 0.000 description 2
- 229940035049 sorbitan monooleate Drugs 0.000 description 2
- 235000011069 sorbitan monooleate Nutrition 0.000 description 2
- 229960005078 sorbitan sesquioleate Drugs 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 239000012588 trypsin Substances 0.000 description 2
- 239000001993 wax Substances 0.000 description 2
- ALSTYHKOOCGGFT-KTKRTIGZSA-N (9Z)-octadecen-1-ol Chemical compound CCCCCCCC\C=C/CCCCCCCCO ALSTYHKOOCGGFT-KTKRTIGZSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- BOSAWIQFTJIYIS-UHFFFAOYSA-N 1,1,1-trichloro-2,2,2-trifluoroethane Chemical compound FC(F)(F)C(Cl)(Cl)Cl BOSAWIQFTJIYIS-UHFFFAOYSA-N 0.000 description 1
- FUFLCEKSBBHCMO-UHFFFAOYSA-N 11-dehydrocorticosterone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 FUFLCEKSBBHCMO-UHFFFAOYSA-N 0.000 description 1
- KZDCMKVLEYCGQX-UDPGNSCCSA-N 2-(diethylamino)ethyl 4-aminobenzoate;(2s,5r,6r)-3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid;hydrate Chemical compound O.CCN(CC)CCOC(=O)C1=CC=C(N)C=C1.N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 KZDCMKVLEYCGQX-UDPGNSCCSA-N 0.000 description 1
- RFVNOJDQRGSOEL-UHFFFAOYSA-N 2-hydroxyethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCO RFVNOJDQRGSOEL-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-M 3-carboxy-2,3-dihydroxypropanoate Chemical class OC(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-M 0.000 description 1
- XZIIFPSPUDAGJM-UHFFFAOYSA-N 6-chloro-2-n,2-n-diethylpyrimidine-2,4-diamine Chemical compound CCN(CC)C1=NC(N)=CC(Cl)=N1 XZIIFPSPUDAGJM-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- 229930000680 A04AD01 - Scopolamine Natural products 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 229930003347 Atropine Natural products 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- VOPWNXZWBYDODV-UHFFFAOYSA-N Chlorodifluoromethane Chemical compound FC(F)Cl VOPWNXZWBYDODV-UHFFFAOYSA-N 0.000 description 1
- MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 description 1
- MFYSYFVPBJMHGN-UHFFFAOYSA-N Cortisone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 MFYSYFVPBJMHGN-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- HEBKCHPVOIAQTA-QWWZWVQMSA-N D-arabinitol Chemical compound OC[C@@H](O)C(O)[C@H](O)CO HEBKCHPVOIAQTA-QWWZWVQMSA-N 0.000 description 1
- MQJKPEGWNLWLTK-UHFFFAOYSA-N Dapsone Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=C1 MQJKPEGWNLWLTK-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 239000004386 Erythritol Substances 0.000 description 1
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 description 1
- RKUNBYITZUJHSG-UHFFFAOYSA-N Hyosciamin-hydrochlorid Natural products CN1C(C2)CCC1CC2OC(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-UHFFFAOYSA-N 0.000 description 1
- STECJAGHUSJQJN-GAUPFVANSA-N Hyoscine Natural products C1([C@H](CO)C(=O)OC2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-GAUPFVANSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241001072332 Monia Species 0.000 description 1
- STECJAGHUSJQJN-UHFFFAOYSA-N N-Methyl-scopolamin Natural products C1C(C2C3O2)N(C)C3CC1OC(=O)C(CO)C1=CC=CC=C1 STECJAGHUSJQJN-UHFFFAOYSA-N 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 239000004264 Petrolatum Substances 0.000 description 1
- LRJOMUJRLNCICJ-JZYPGELDSA-N Prednisolone acetate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)C[C@@H]2O LRJOMUJRLNCICJ-JZYPGELDSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- RKZXQQPEDGMHBJ-LIGJGSPWSA-N [(2s,3r,4r,5r)-2,3,4,5,6-pentakis[[(z)-octadec-9-enoyl]oxy]hexyl] (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCC\C=C/CCCCCCCC)[C@@H](OC(=O)CCCCCCC\C=C/CCCCCCCC)[C@H](OC(=O)CCCCCCC\C=C/CCCCCCCC)[C@@H](OC(=O)CCCCCCC\C=C/CCCCCCCC)COC(=O)CCCCCCC\C=C/CCCCCCCC RKZXQQPEDGMHBJ-LIGJGSPWSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 230000001780 adrenocortical effect Effects 0.000 description 1
- 230000003023 adrenocorticotropic effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 238000012387 aerosolization Methods 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 150000001348 alkyl chlorides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000000954 anitussive effect Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 230000001166 anti-perspirative effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 239000003213 antiperspirant Substances 0.000 description 1
- 229940124584 antitussives Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- RKUNBYITZUJHSG-SPUOUPEWSA-N atropine Chemical compound O([C@H]1C[C@H]2CC[C@@H](C1)N2C)C(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-SPUOUPEWSA-N 0.000 description 1
- 229960000396 atropine Drugs 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229940124630 bronchodilator 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
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- KYKAJFCTULSVSH-UHFFFAOYSA-N chloro(fluoro)methane Chemical compound F[C]Cl KYKAJFCTULSVSH-UHFFFAOYSA-N 0.000 description 1
- CYDMQBQPVICBEU-UHFFFAOYSA-N chlorotetracycline Natural products C1=CC(Cl)=C2C(O)(C)C3CC4C(N(C)C)C(O)=C(C(N)=O)C(=O)C4(O)C(O)=C3C(=O)C2=C1O CYDMQBQPVICBEU-UHFFFAOYSA-N 0.000 description 1
- CYDMQBQPVICBEU-XRNKAMNCSA-N chlortetracycline Chemical compound C1=CC(Cl)=C2[C@](O)(C)[C@H]3C[C@H]4[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]4(O)C(O)=C3C(=O)C2=C1O CYDMQBQPVICBEU-XRNKAMNCSA-N 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229960004126 codeine Drugs 0.000 description 1
- 229960001338 colchicine Drugs 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 229960004544 cortisone Drugs 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000002178 crystalline material Substances 0.000 description 1
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- LVYZJEPLMYTTGH-UHFFFAOYSA-H dialuminum chloride pentahydroxide dihydrate Chemical compound [Cl-].[Al+3].[OH-].[OH-].[Al+3].[OH-].[OH-].[OH-].O.O LVYZJEPLMYTTGH-UHFFFAOYSA-H 0.000 description 1
- UMNKXPULIDJLSU-UHFFFAOYSA-N dichlorofluoromethane Chemical compound FC(Cl)Cl UMNKXPULIDJLSU-UHFFFAOYSA-N 0.000 description 1
- 229940099364 dichlorofluoromethane Drugs 0.000 description 1
- 229940099212 dilaudid Drugs 0.000 description 1
- PCHPORCSPXIHLZ-UHFFFAOYSA-N diphenhydramine hydrochloride Chemical compound [Cl-].C=1C=CC=CC=1C(OCC[NH+](C)C)C1=CC=CC=C1 PCHPORCSPXIHLZ-UHFFFAOYSA-N 0.000 description 1
- DLNKOYKMWOXYQA-UHFFFAOYSA-N dl-pseudophenylpropanolamine Natural products CC(N)C(O)C1=CC=CC=C1 DLNKOYKMWOXYQA-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229960002179 ephedrine Drugs 0.000 description 1
- 229960004943 ergotamine Drugs 0.000 description 1
- OFKDAAIKGIBASY-VFGNJEKYSA-N ergotamine Chemical compound C([C@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@@](C(N21)=O)(C)NC(=O)[C@H]1CN([C@H]2C(C3=CC=CC4=NC=C([C]34)C2)=C1)C)C1=CC=CC=C1 OFKDAAIKGIBASY-VFGNJEKYSA-N 0.000 description 1
- XCGSFFUVFURLIX-UHFFFAOYSA-N ergotaminine Natural products C1=C(C=2C=CC=C3NC=C(C=23)C2)C2N(C)CC1C(=O)NC(C(N12)=O)(C)OC1(O)C1CCCN1C(=O)C2CC1=CC=CC=C1 XCGSFFUVFURLIX-UHFFFAOYSA-N 0.000 description 1
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 description 1
- 235000019414 erythritol Nutrition 0.000 description 1
- 229940009714 erythritol Drugs 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 description 1
- 229960001410 hydromorphone Drugs 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 150000002484 inorganic compounds Chemical class 0.000 description 1
- 229910010272 inorganic material Inorganic materials 0.000 description 1
- 238000002642 intravenous therapy Methods 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 229940018448 isoproterenol hydrochloride Drugs 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 229960001869 methapyrilene Drugs 0.000 description 1
- HNJJXZKZRAWDPF-UHFFFAOYSA-N methapyrilene Chemical compound C=1C=CC=NC=1N(CCN(C)C)CC1=CC=CS1 HNJJXZKZRAWDPF-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000002052 molecular layer Substances 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- SNMVRZFUUCLYTO-UHFFFAOYSA-N n-propyl chloride Chemical class CCCCl SNMVRZFUUCLYTO-UHFFFAOYSA-N 0.000 description 1
- 239000002120 nanofilm Substances 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- 150000002889 oleic acids Chemical class 0.000 description 1
- 229940055577 oleyl alcohol Drugs 0.000 description 1
- XMLQWXUVTXCDDL-UHFFFAOYSA-N oleyl alcohol Natural products CCCCCCC=CCCCCCCCCCCO XMLQWXUVTXCDDL-UHFFFAOYSA-N 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000011368 organic material Substances 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-N palmitic acid group Chemical group C(CCCCCCCCCCCCCCC)(=O)O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 229940066842 petrolatum Drugs 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 229960000395 phenylpropanolamine Drugs 0.000 description 1
- DLNKOYKMWOXYQA-APPZFPTMSA-N phenylpropanolamine Chemical compound C[C@@H](N)[C@H](O)C1=CC=CC=C1 DLNKOYKMWOXYQA-APPZFPTMSA-N 0.000 description 1
- 229940068886 polyethylene glycol 300 Drugs 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 229960002800 prednisolone acetate Drugs 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000009877 rendering Methods 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- STECJAGHUSJQJN-FWXGHANASA-N scopolamine Chemical compound C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-FWXGHANASA-N 0.000 description 1
- 229960002646 scopolamine Drugs 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000344 soap Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 229940035044 sorbitan monolaurate Drugs 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- IWVCMVBTMGNXQD-UHFFFAOYSA-N terramycin dehydrate Natural products C1=CC=C2C(O)(C)C3C(O)C4C(N(C)C)C(O)=C(C(N)=O)C(=O)C4(O)C(O)=C3C(=O)C2=C1O IWVCMVBTMGNXQD-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 229960001322 trypsin Drugs 0.000 description 1
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 1
- 230000003639 vasoconstrictive effect Effects 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
Classifications
-
- 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
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
- A01N25/02—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests containing liquids as carriers, diluents or solvents
- A01N25/04—Dispersions, emulsions, suspoemulsions, suspension concentrates or gels
- A01N25/06—Aerosols
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
- C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
- C11D17/00—Detergent materials or soaps characterised by their shape or physical properties
- C11D17/0043—For use with aerosol devices
Definitions
- This invention relates to self-propelling. power-dispensing compositions capable of dispensing powdered material in aerosol form and to a means for dispensing a dry powder in aerosol form having controlled particle size.
- compositions of the invention comprise a finely-divided active solid material or powder suspended in a liquified propellant, in which the solid material is substantially insoluble, and a non-ionic surface-active agent which is liquid at room temperature (65 F.), or ambient temperatures.
- he finely divided powder may constitute from about 0.01 to 20% by weight of the total composition. Desirably it shall constitute from about 0.05% to 10%, and referably 0.1 to 3%, by weight of the total composition.
- the surface-active agent may constitute from about 0.1 to 20%, desirably between about 0.25 and 5%, and preferably, for medicinal purposes, between about 0.25 and 1%, by weight of the total composition, with the liquified propellant constituting the remainder of the composition.
- the concentration of surfaceactive'agent is kept at a minimum as it may tend to solubilize the powder in the propellant, which is undesirable for reasons which will be explained below.
- the particle-size of the powder should desirablybe uniform and not greater than microns diameter, since larger particles may tend to agglomerate, separate from the suspension and may clog thevalve or orifice. of the container.
- the particle size should be less than 25- microns in diameter.
- the. particlesize of the finely-divided solid powder should for physiological reasons be less than 25 microns and preferably less than 10 microns in diameter.
- the size of the particles of powder should be substantially uniform. There is no lower limit of particle size except'that'which is imposed by the use to which the aerosol produced is to be put. Where the powder is a solid medicament, the lower limit of particle size is that which will be readily absorbed and retained on or in body tissues. When particles less than one micron in diameter are administered by inhalation they tend to be re-exhaled by the patient.
- the finely-divided powder should be substantially insoluble in each of the liquified propellant, the surface-active agent and in a liquified propellant-surface-active mixture.
- the powder is substantially soluble, crystal growth may occur and the particle size of the aerosolized powder when dispensed cannot be controlled.
- compositions of the invention are intended to be used for dispensing powders in aerosol form by operating the valve of a pressuretight container charged with the compositions, it is desirable that the particle size of the suspended powder be regulated and agglomeration reduced. It is clear that if agglomeration of the powder takes place, it may tend to clog the narrow valve orifice and render the dispensing device inoperative, or it a metering valve is employed, it may be rendered inaccurate. This may lead to inaccurate dosages, which in the case of highly potent medicinals may lead to undesirable results. In addition to increasing 3 make the suspension unstable and of unsuitable appearance. In the case of powdered medicinals, adsorption in the body may be made ineffective. Consequently, it is desirable that the finely-divided powder be substantially insoluble in the other components of the compositions.
- a finely-divided powder such as a medicament
- a finely-divided powder tends to be somewhat soluble in the mixture of surfaceactive agent and liquified propellant
- a less soluble form of the powder For example, instead of employing the base phenylephrine, its hydrochloride may .be employed.
- different liquified propellants may be employed in which the powder is less solubie.
- compositions of the invention Illustrative of the versatility of the compositions of the invention is the fact that the solid components may be amorphous or crystalline in nature. We prefer to use crystalline materials, as is indicated by the specific examples given below. Early efforts to produce self-propelling powder dispensing compositions showed that even to obtain compositions having only borderline properties, it was necessary to limit the solid materials employed to amorphous materials.
- compositions of the present invention do not require the presence of a polar solvent, such as water.
- a polar solvent such as water.
- the compositions may be substantially anhydrous.
- moisture control is important at all stages of processing.
- Another means of controllingand reducing the moisture content of the composition is to introduce before closing the container in which the composition is packaged, small fragments of an anhydrous, nonreactive desiccant, such as silica gel or calcium sulfate. This reduces the moisture content of the liquid phase of the composition below that which causes agglomeration.
- an anhydrous, nonreactive desiccant such as silica gel or calcium sulfate. This reduces the moisture content of the liquid phase of the composition below that which causes agglomeration.
- desiccant is sutficien-t for a 10 ml. container charged with composition.
- the solid active component to be aerosolized may be a: medicament, such as a vasoconstrictive amine or its acid-addition salts, a hormone, enzyme, alkaloid, steroid, analgesic, bronchodilator, antihistamine, antitussive, an-
- medicament such as a vasoconstrictive amine or its acid-addition salts, a hormone, enzyme, alkaloid, steroid, analgesic, bronchodilator, antihistamine, antitussive, an-
- medicaments which may be employed are: isoproterenol [alpha- (isopropylaminomethyl)protocatechuyl alcohol] hydro- .chloride or sulfate, phenylephrine, phenylpropanolamine,
- glucagon adrnochrome, trypsin, epinephrine, ephedrine, narcotine, codeine, atropine, morphine, dihydromorphinone, ergotamine, scopolamine, methapyrilene, cyanocobalamin, and colchicine.
- Others are antibiotics such as ncomycin, streptomycin, penicillin, procaine penicillin, tetracycline, chlorotetracycline and hydroxytetracycline;
- the active solid component may also be a cosmetic substance such as talc, an antiperspirant such as aluminum chlorohydrate,
- a lubricant such as graphite and other finely-divided materials; as well as other usefulsubstances.
- the liquified propellant employed is one which is a gas at room temperature (65 F.) and atmospheric pressure (760 mm. of mercury), i.e., it shall have a boiling point below 65 F. at atmospheric pressure.
- the liquified propellant should be non-toxic.
- suitable liquitied propellants which may be employed are the lower alkanes containing up to five carbon atoms, such as butane and pentane, or a lower alkyl chloride, such as methyl, ethyl or propyl chlorides.
- the most suitable liquified propellants are the fiuorinated aand fiuorochlorinated lower alkanes such as are sold under the trademark Freon. Mixtures of the above mentioned propellants may suitably be employed.
- the fiuorinated or flLlOIOChiOI'b nated lower alkane shall contain not more than two carhon atoms and at least one fluorine atom.
- Examples of these propellants are dichlorodifluoromethane (Freon l2), dichlorotetrafiuoroethane (Freon 1 l4) CClF .CC1F trichloromonofiuoromethane (Freon 11), dichloromonofluoromethane (Freon 2l) monochloroditluoromethane (Freon 22), trichlorotrifluoroethane (Freon 113), and monochlorotrifluorm methane (Freon l3).
- Propellants with improved vapor pressure characteristics may be obtained by using certain mixures of these compounds, e.g., Freon 11" with Freon 12, or Freon 12" with Freon 114.”
- the vapor pressure of the propellant employed shall itself be Between about 25 and 65 pounds per square inch gauge at 70 F., arid prefer bly between about 30 and 40 pounds per square inch gauge at that temperature.
- a one-component propellant defined for use in the composition was found to give a composition with gauge pressures in the range of 55 to 65 pounds per square inch at 70 R, which are usable safely with metal containers.
- the two-component propellants such as equal weight mixtures of "Freon 12 and Freon 11, were found to give gauge pressures in the range of 20 to 40 pounds per square inch at 70 R, which are usable safely with specially reinforced glass containers.
- valves of simple construction may be used, and there is no need to provide special nozzles and expansion chambers, as is usually required when dispensing materials surface coating, which may even be a mono-molecular film or layer, on the finely-divided powder which prevents the particles from agglomerating either while dispersed in the propellant or when in the valve of the container.
- the liquid, non-ionic, surface-active agent employed should have an hydrophile-lipophile balance (HLB) ratio of less than 10.
- HLB ratio is an empirical number which provides a guide to the surface-active properties of a surface-active agent. The lower the HLB ratio, the more lipophilic is the agent, and conversely, the higher the HLB ratio, the more hydrophiiic is the agent.
- the HLB ratio is well known and understood by the colloid chemist and its method of determination is described by W. C. Grifiin in the Journal of the Society of Cosmetic Chemists, vol. 1, No. 5, pages 311-326 (1949).
- the surface-active agent employed should have an HLB ratio of about 1 to 5. It is possible to employ surface-active agents which themselves do not possess an HLB ratio within these ranges, providing they are used in conjunction with other surface-active agents which have an HLB ratio which will provide a mixture having an HLB ratio within the prescribed range.
- Lubricants for the valve such as calcium stearate, which is without surfactant properties, were not found to be satisfactory, because they do not help to keep the powdered medicament uniformly dispersed in the pro pellant.
- the surfaceactive agent should be non-irritating and non-toxic.
- liquid non-ionic surfaceactive agents which may be employed in our compositions are the esters or partial esters of fatty acids containing from 6 to 22 carbon atoms, such as caproic, octoic, lauric, palmitic, stearic, linoleic, linolenic, eleostearic and oleic acids with an aliphatic polyhydric alcohol or its cyclic anhydride such as, for example, ethylene glycol, glycerol, erythritol, arabitol, mannitol, sorbitol, the hexitol anhydrides derived from sorbitol (the sorbitan esters sold under the trademark Spans”) and the polyoxyethylene and polyoxypropylene derivatives of these esters.
- an aliphatic polyhydric alcohol or its cyclic anhydride such as, for example, ethylene glycol, glycerol, erythritol, arabitol, manni
- sorbitan e.g., those sold under the trademarks Arlacel C (Sorbitan sesquioleate), Span 80 (sorbitan monooleate) and Span 85 (sorbitan trioleate).
- MYRJ 45 Polyoxyethylene Very good suspension, elumpy, stearate. sticks to container, breaks very rapidly, lubrieates valve.
- Bi-i Polyoxyctliylenelauryl Very poor suspension, clumpy,
- compositions of the invention employing certain finely-divided powders there is a tendency to form a layer of powder at the surface of the propellant in the container and that these layers tend to deposit or cake" powdered material on the container walls above the liquid level. This has been found to occur only with those powders which have a specific gravity less than that of the propellant.
- the undesirable deposition or caking which results where the specific gravity of the finely divided powder is substantially less than that of the propellant can be overcome by lowering the specific gravity of the liquid phase, for example by using a propellant of lower specific gravity, such as butane, or by increasing the specific gravity of the solid active powder component, for example in the case of phenylephrine by using the bitartrate salt instead of hydrochloride.
- a propellant of lower specific gravity such as butane
- the specific gravity of the solid active powder component for example in the case of phenylephrine by using the bitartrate salt instead of hydrochloride.
- auxiliary solid may be of any chemical type, provided that it is compatible with the other ingredients and insoluble in the propellant.
- an inorganic compound such as sodium sulfate, calcium chloride or sodium chloride.
- an organic material such as powdered lactose, sucrose, epinephrine bitartrate, neomycin sulfate, or graphite.
- the auxiliary solid when used in medicinal and cosmetic preparations, should be non-toxic and nonirritant. In all cases it should be without deleterious effect on the properties of the dispensed product or on the user.
- the particle size of the auxiliary solid should pp in this suitable for inhalation therapy.
- PU is equal to or greater than pp (3) thus when q equals 11, equals zero. less than [312, the following exists:
- compositions of the invention may-be used to apply measured amounts of aerosolized solid medicaments into body cavities such as the throat or nose. They also provide a means of producing aerosolized medicaments Inhalation therapy is prompt through the intimate contact with the blood through the alveolar membrance. It also enablm drugs to act directly on respiratory sites without engendering undesirable systemic effects as happens often When drugs are administered by other routes. With very volatile substances inhalation approaches intravenous therapy in rapidity of. action. It willoften avoid the necessity of parenteral injections.- Previously aerosols for this purpose have been prepared by nebulizing aqueous solutions,
- a container equipped with a valve is filled with a propellant containing the finely-divided powder in suspension.
- a container may first be charged with a weighed amount of dry powder which has been ground to a predetermined particle size, or in a slurry of powder in the cooled liquid propellant.
- the powder and the surface-active agent may be triturated or homogenized first into a uniform paste, for instance, by a pestle and mortar. This paste is then dispersed in the cooled liquefied propellant. This procedure fosters uniform wetting of the powder particles.
- a container may also be filled by introducing powder and propellant by the normal cold filling method, or a slurry of the powder in that component of the propellant which boils above room temperature may be placed in the container, the valve sealed in place, and the balance of the propellant may be introduced by pressure filling through the valve nozzle.
- the powder On operating the valve, the powder will be dispensed in a stream of propellant, which will vaporize providing an aerosol of dry powder.
- the preparation of the product care is desirably exercised to minimize the absorption of moisture where the powder is water-soluble. This may be accomplished by operat-' .ing in a dehumidified atmosphere using only dry materials and equipment.
- Example 1 Percent Hydrocortisone acetate, crystalline (more than 90% by weight within the particle size range of l to 5 microns) 3.0 Span 85 (sorbitan trioleate) 1.0 Freon l1 (trichloromonofluoromethane) 30.0 Freon 114 (dichlorotetrafiuoroethane) 41.0 Freon 12 (dichlorodifiuoromethane) 25.0
- Example 2 Gm. Trypsin, amorphous (more than 90% by weight within the particle size range of l to 10microns) 0.10
- Example 3 Percent Pre dnisolone acetate, crystalline (more than 90% by weight within the particle size range of l to 5 microns) 0.5 Span 85 (sorbitan trioleate) 0.5 Propellant B 99.0
- Prcpellant B consists of:
- Freon 11 (trichloromoncfiuoromethane) 10.0 Freon 114 (dichlorotetrafluorcethane) 50.4 Freon 12" (dichlorctetrafluoroethanc) 31.6 Butane a; 8.0
- Example 4 ACTH (adrenocorticotropin) (amorphous) (l USP units/mg.) (more than 90% by weight within the particle size range, of 1 to 20 micron's) N 1.00
- Insulin amorphous (more than 90% by weight I within the particle size range of 1 to 5 microns) 0.25 Span 85 (sorbitan trioleate) 0.25 Freon W (as defined in Example 2) 99.50
- Example 7 Epinephrine, crystalline (free base) (more than 90% by weight within the particle size range of 1 to 5 microns 0.28 Span 85 (sorbitan. trioleate) 0.25 Freon 11 (trichlorornonofluorometha-ne) 5.00
- Example 8 Epinephrine bitartrate, crystalline (more than 90% by weight withinthe particle size range of 1 to 5 microns) 0.50 Span 85(sorbitan trioleate) 0.50 Freon 11"'(trichloromonofluoromethane) 49.50 Freon '12 (dichlorodifluoromethane) .l- 49.50
- Example 9 Isopropylarterenol hydrochloride, crystalline (more than 90% by weight within the particle size range of l to 5 microns) 0.25 Span (sorbitan trioleate) 0.25 Freonll (trichlorornonofluoromethane) 49.75 Freon l2 (dichlorodifiuorcmethane) 49.75
- Example 10 Phenylephrine hydrochloride, crystal-line (more than by weight within the particle size range of l to 25 microns) 0.25 Ncomycin sulfate 0.11 Hydrowrtisone 0.04 Span S5" (sorbitan trioleate) 0.25 Freon ll (trichloromonofiuoromethane) 49.675 Freon l2 (dichlorodifluorornethane) 49.675
- Example 12 Hydrocortisene acetate, crystalline (more than 90% by weight within the particle size range 'of l to 5 microns) 0.50
- Surfactant 6-1087 polyoxyethylene sorbitol hexaoleate
- a, 0.50 Propcllant C 99.00
- Example 13 Percent Hydrocortisone acetate, crystalline (more than 90% by weight within the particle size range of 1 to 5 microns) 0.50 Arlacel C (sorbitan sesquioleate) 0.50 Propellant C (as defined by Example 12) 99.00
- Example 14 Hydrocortisone acetate, crystalline (more than 90% by weight within the particle size range of 1 to 5 microns) 0.50 Span 80 (sorbitan monoleate) 0.50 Propellan-t- C (as defined-by Example 12) 99.00
- Example 15 Hydrocortisone acetate, crystalline (more than 90% by weight within the particle size range of 1 to 5 microns) 0.50 Span S5 (sorbitan trioleate) 0.50 Propellant C-(as defined by Example 12) 99.00
- Narcotine crystalline (more than 90% by weight within the particle size range of 1 to microns) 10.00 Span 85 (sorbitan trioleate) 1.00 Freon W (as defined by Example 2) 89.00
- Example 17 "Dilaudid, crystalline (dihydrornorphinone hydrochloride) (more than 90% by weight within the particle size range of 1 to 5 microns) 0.5 Span 85 (sorbitan trioleate) 1.0 Freon 11 (trichloromonofiuoromethane) 30.0 Freon W" (as defined by Example 2) 68.5
- This composition is useful for polishing optical components.
- Example 19 Percent Hydrocortisone acetate, crystalline (more than 90% 'by weight within the particle size range of 1 to 5 microns) 0.5 Olive oil 0.5 Freon 11 30.0 Freon W (as defined by Example 2) 69.0
- Example 20 Phenylephrine hydrochloride (crystalline), micronized 0.25 Phenylpropanolamine hydrochloride (crystalline), micronized 0.50 'Neomycin sulfate (crystalline), micronized 0.10 Hydrocortisone (crystalline), micronized 0.04 Sodium sulfate (anhydrous), micronizcd 0.35 Span 85" (sorbitan trioleate) 0.80 Prd'pellant S 97.96
- Propellant S consists of:
- Example 25 Phcnylephrine hydrochloride (crystalline), micronized 1.0 Neomycin sulfate (crystalline), micronized 3.0 Span 85 (sorbitan trioleate) 1.0 Propellant S (as defined by Example 20) 95.0
- Propellant S-2 consists of:
- Neomycin sulfate (crystalline), micronized 0.08
- Propellant X consists of:
- Freon 12 (dichlorodifluoromethane) 30 Freon 11 (trichloromonofiuoromethane) 30 Freon 114 (dichlorotetrafluoroethane) 40
- Phenylephn'ne hydrochloride (c ystalline), mi-
- Neomycin sulfate crystalline
- micronized 0.08 Thenylpy'ramine hydrochloride crystalline
- Example 31 Isoproterenol sulfate, crystalline, micronized 0.15 Span 85 (sorbitan trioleate) 0.50 Freon 113 (trichlorotrifiuoroethane) 0.95 Freon 11 (trichloromonofiuoromethane) 24.60 Freon 114 (dichlorotetrafluoroethane) 24.60 Freon 12 (dichlorodifiuoromethane) 49.20
- Example 34 Crystalline glucagon, micronized 0.156 "Span 85- 0.468 Propellant S" (as defined by Example 20) 99.376
- Example 35 Anhydrous cyanocobalamin, crystalline, micronized 0.039 Span 85 0.25 Propellant S (as defined by Example 20) 99.711
- Example 36 Chlorotetracycline hydrochloride, crystalline, mi-
- Example 37 Adrenochrome, crystalline, micronized 1.785 Span 85 Propellant S" (as defined by Example 20) 97.215
- a self-propelling, powder dispensing composition capable of producing a useful substance in aerosol form comprising between about 0.01% and 20% by weight of a finely-divided powder of a particle size less than about microns suspended in a liquefied propellant having a vapor pressure of at least about 13 lbs.
- said composition shall contain not more than about 300 parts per million of moisture.
- a self-propelling, powder dispensing composition as defined by claim 8 wherein the finely-divided powder comprises isoproterenol hydrochloride.
- a self-propelling, powder dispensing pharmaceutical composition capable of providing a medicament in aerosol form suitable for inhalation therapy, comprising a liquefied non-toxic propellant having a vapor pressure of at least about 13 lbs. per square inch gauge at 70 F., between about 0.01% and 20% by weight of a finelydivided therapeutically active powdered medicament of substantially uniform particle size of less than about 100 microns suspended in said propellant, and between about 0.1% and 20% by weight of a liquid non-toxic non-ionic surface active agent having a hydrophile-lipophile balance ratio of less than about 10 and being soluble in said liquefied propellant; said finely-divided powder being substantially insoluble in the mixture of propellant and surface active agent; and when said finely-divided powder is watersoluble, said composition shall contain not more than about 300 parts per million of moisture.
- a self-propelling, powder dispensing composition capable of producing a useful substance in aerosol form comprising a composition as defined in claim 1, wherein the specific gravity of the finely divided powder is at least as great as that of the liquefied propellant.
- a self-propelling, powder dispensing composition capable of producing a useful substance in aerosol form comprising a composition as defined by claim 1 having "11 units by weight of a useful substance of specific gravity as a finely-divided powder and aunits by weight of an auxiliary solid substance of specific gravity p in powdered form suspended in a liquid of specific gravity pp wherein the minimum value of is expressed as follows:
- a self-propelling powder dispensing composition capable of producing a useful substance in aerosol form according to claim 22', wherein the auxiliary solid is sodium sulfate.
- a self-propelling, powder dispensing composition capable of producing a useful substance in aerosol form according to claim 22, wherein the auxiliary solid is calcium chloride.
- a self-propelling, powder dispensing composition capable of producing a useful substance in aerosol form according to claim 22, wherein the auxiliary solid is lactose.
- a self-propelling, powder dispensing composition capable of producing a useful substance in aerosol form according to claim 22, wherein the auxiliary solid is sucrose.
- a package comprising a pressure-tight container having a valve-controlled opening and containing alpharmaceutical composition capable of providing a measured dose of medicament in aerosol form suitable for inhalation therapy, comprising a composition as defined by claim 20 31.
- pages 324, 328 read pages 324 through 328 Signed and sealed this 24th day of April 1962.
- pages 324, 328 read pages 324 through 328 Signed and sealed this 24th day of April 1962.
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Dispersion Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Wood Science & Technology (AREA)
- Toxicology (AREA)
- Materials Engineering (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Pest Control & Pesticides (AREA)
- Plant Pathology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Dentistry (AREA)
- Zoology (AREA)
- Environmental Sciences (AREA)
- Agronomy & Crop Science (AREA)
- Otolaryngology (AREA)
- Pulmonology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Preparation (AREA)
Description
Ute.
States atent Ofihce 3,014,844 SELF-PROPELLING POWDER DISPENSING I COMPGSITIQNS Charles G. Thicl, Santa Monica, Irving Porush, Los Angeles, and Ronald D. Law, La Mirada, Caliti, assignors to Riker Laboratories, Inc, Los Angeics, Califl, a corporation of Delaware No Drawing. Filed Jan. 3, 1958, Ser. No. 706,908 31 Claims. (Cl. 167--82) This application is a continuation-in-part of our copending application, Serial No. 680,016, filed August 23, 1957, which is in turn a continuation-in-part of our prior application, Serial No. 637,353, filed January 31, 1957, both now abandoned.
This invention relates to self-propelling. power-dispensing compositions capable of dispensing powdered material in aerosol form and to a means for dispensing a dry powder in aerosol form having controlled particle size.
Previously it has not been possible to provide stable suspensions of powder of substantially uniform particle size in a liquified propellant for use in a pressurized container for aerosol dispensing which would not cause the closure valve, and particularly a metering valve, to
.stick. It has generally been the practice to prepare selfpropelling compositions'for aerosol administration by rendering the solid, active ingredient soluble in the liquified propellant by means of a coso-lvent. Usually the cosolvent is polar in character, e.g.,' alcohol. Unfortunately many solids, and particularly certain medicaments,
,are notfstable in polarsolvents such as water, or they are rendered unstable when in a polar solvent and incon- .tact with the metal of which the valve of a pressure-tight container is usually constructed. This is the case with epinephrine. These polar solvent-containing systems may also attack and corrode the metal valve closures of the containers and interfere with their functioning. Also,
some medicaments and other solids cannot be satisfao I torily solubilized in the usual liquified propellants, even though a cosolvent is employed. By means of-the present invention it is possible to overcome these shortcomings of the prior art and to provide simple, more stable and more satisfactory aerosol-producing compositions.
It is an object of this invention to provide a package from which a dry powder may be dispensed as an aerosol in a stream of moving gas in a controlled manner or in metered quantities.
It is a further object of the present invention to provide stable suspension compositions of powdered solids which may be dispensed effectively and efficiently in aerosol form in measured quantities, wherein the compositions remain substantially homogeneous and attractive in ap pearance during storage.
It is another object to provide stable therapeutic compositions which are self-propelling and which may be dispensed consistently in accurate doses through a metering valve for inhalation therapy without causing toxic or irritating side effects on the user.
It is an additional object of the present invention to provide stable self-propelling suspension compositions of powdered solids with reduced tendency to deposit on the container walls above the liquid level or cake out.
It is also an object to provide a method for efliciently and effectively dispensing a dry powder in aerosol form of controlled particle size in a manner which avoids sedimentation and particle agglomerization or interference PatentedDec. 26, 1961 with the functioning of the valve closure and metering mechanisms.
Other objects will be apparent to those skilled in the art from reading the following description.
The self-propelling, powder-dispensing compositions of the invention comprise a finely-divided active solid material or powder suspended in a liquified propellant, in which the solid material is substantially insoluble, and a non-ionic surface-active agent which is liquid at room temperature (65 F.), or ambient temperatures.
he finely divided powder may constitute from about 0.01 to 20% by weight of the total composition. Desirably it shall constitute from about 0.05% to 10%, and referably 0.1 to 3%, by weight of the total composition. The surface-active agent may constitute from about 0.1 to 20%, desirably between about 0.25 and 5%, and preferably, for medicinal purposes, between about 0.25 and 1%, by weight of the total composition, with the liquified propellant constituting the remainder of the composition. For, best results, the concentration of surfaceactive'agent is kept at a minimum as it may tend to solubilize the powder in the propellant, which is undesirable for reasons which will be explained below.
We have discovered that considerable deviation is permissible if the particle size of the powder is small enough. For pharmaceutical purposes the particle-size of the powder should desirablybe uniform and not greater than microns diameter, since larger particles may tend to agglomerate, separate from the suspension and may clog thevalve or orifice. of the container. Preferably the particle size should be less than 25- microns in diameter. Desirably. the. particlesize of the finely-divided solid powder should for physiological reasons be less than 25 microns and preferably less than 10 microns in diameter. For best results, the size of the particles of powder should be substantially uniform. There is no lower limit of particle size except'that'which is imposed by the use to which the aerosol produced is to be put. Where the powder is a solid medicament, the lower limit of particle size is that which will be readily absorbed and retained on or in body tissues. When particles less than one micron in diameter are administered by inhalation they tend to be re-exhaled by the patient.
Desirably the finely-divided powder should be substantially insoluble in each of the liquified propellant, the surface-active agent and in a liquified propellant-surface-active mixture. In the majority of cases wefind that solid compounds which are predominantly polar in nature by reason of a sufiicient number of polar substituent groups such as hydroxyl, amino and carboxyl groups, and salts thereof, provide most satisfactory compositions in accordance with the invention. It the powder is substantially soluble, crystal growth may occur and the particle size of the aerosolized powder when dispensed cannot be controlled. Since the compositions of the invention are intended to be used for dispensing powders in aerosol form by operating the valve of a pressuretight container charged with the compositions, it is desirable that the particle size of the suspended powder be regulated and agglomeration reduced. It is clear that if agglomeration of the powder takes place, it may tend to clog the narrow valve orifice and render the dispensing device inoperative, or it a metering valve is employed, it may be rendered inaccurate. This may lead to inaccurate dosages, which in the case of highly potent medicinals may lead to undesirable results. In addition to increasing 3 make the suspension unstable and of unsuitable appearance. In the case of powdered medicinals, adsorption in the body may be made ineffective. Consequently, it is desirable that the finely-divided powder be substantially insoluble in the other components of the compositions.
Where a finely-divided powder, such as a medicament, tends to be somewhat soluble in the mixture of surfaceactive agent and liquified propellant, it is sometimes possi- 'ble to overcome this difficulty by employing a less soluble form of the powder. For example, instead of employing the base phenylephrine, its hydrochloride may .be employed. Also, different liquified propellants may be employed in which the powder is less solubie.
Illustrative of the versatility of the compositions of the invention is the fact that the solid components may be amorphous or crystalline in nature. We prefer to use crystalline materials, as is indicated by the specific examples given below. Early efforts to produce self-propelling powder dispensing compositions showed that even to obtain compositions having only borderline properties, it was necessary to limit the solid materials employed to amorphous materials.
As will be apparent to those skilled in the art, one of the advantages of the compositions of the present invention is that they do not require the presence of a polar solvent, such as water. The compositions may be substantially anhydrous.
in carrying out the present invention, especially where water-soluble medicaments are employed, we have discovered that moisture control is important at all stages of processing. We have found that the total moisture content for finely-dispersed water-soluble medicaments should be less than 300 parts per million by weight of :total composition. This moisture control has been found to be critical to ensure thestability of the suspension during periods of storage. For instance, in the case of Example hereinbelow, when more than 300 parts per million of water are present, the medicament agglomer= ates withinone month at room temperatureanddeposits on thewalls of the container. This adversely affects the 'dose delivered, in addition to resulting in a pharmaceutically inelegant preparation, Another means of controllingand reducing the moisture content of the composition is to introduce before closing the container in which the composition is packaged, small fragments of an anhydrous, nonreactive desiccant, such as silica gel or calcium sulfate. This reduces the moisture content of the liquid phase of the composition below that which causes agglomeration. Usually 100 mgm. of desiccant is sutficien-t for a 10 ml. container charged with composition.
The solid active component to be aerosolized may be a: medicament, such as a vasoconstrictive amine or its acid-addition salts, a hormone, enzyme, alkaloid, steroid, analgesic, bronchodilator, antihistamine, antitussive, an-
ginal preparation, antibiotic and sulfona'mide and synergetic combinations of these. Examples of the medicaments which may be employed are: isoproterenol [alpha- (isopropylaminomethyl)protocatechuyl alcohol] hydro- .chloride or sulfate, phenylephrine, phenylpropanolamine,
glucagon, adrnochrome, trypsin, epinephrine, ephedrine, narcotine, codeine, atropine, morphine, dihydromorphinone, ergotamine, scopolamine, methapyrilene, cyanocobalamin, and colchicine. Others are antibiotics such as ncomycin, streptomycin, penicillin, procaine penicillin, tetracycline, chlorotetracycline and hydroxytetracycline;
.adrenocorticotropic .hormone, and adrenocortical hormones, 'usch as cortisone, hydrocortisone, hydrocortisone acetate and prednisalone; insulin, etc. The active solid component may also be a cosmetic substance such as talc, an antiperspirant such as aluminum chlorohydrate,
'etc.; a polishing material such as jewelers rouge; a dye,
such as the approved food colorings; a lubricant, such as graphite and other finely-divided materials; as well as other usefulsubstances.
'4 The liquified propellant employed is one which is a gas at room temperature (65 F.) and atmospheric pressure (760 mm. of mercury), i.e., it shall have a boiling point below 65 F. at atmospheric pressure. For use in compositions intended to produce aerosols for medicinal or cosmetic use, the liquified propellant should be non-toxic. Among the suitable liquitied propellants which may be employed are the lower alkanes containing up to five carbon atoms, such as butane and pentane, or a lower alkyl chloride, such as methyl, ethyl or propyl chlorides. The most suitable liquified propellants are the fiuorinated aand fiuorochlorinated lower alkanes such as are sold under the trademark Freon. Mixtures of the above mentioned propellants may suitably be employed.
It is contemplated that the fiuorinated or flLlOIOChiOI'b nated lower alkane shall contain not more than two carhon atoms and at least one fluorine atom. The preferred halogenated lower alkane compounds may be represented generally by the formula C H Cl F wherein Mr is an integer less than 3, n is an integer or zero, y is an integer or zero, and z is an integer, such that n-l-y+z=?.m+2. Examples of these propellants are dichlorodifluoromethane (Freon l2), dichlorotetrafiuoroethane (Freon 1 l4) CClF .CC1F trichloromonofiuoromethane (Freon 11), dichloromonofluoromethane (Freon 2l) monochloroditluoromethane (Freon 22), trichlorotrifluoroethane (Freon 113), and monochlorotrifluorm methane (Freon l3). Propellants with improved vapor pressure characteristics may be obtained by using certain mixures of these compounds, e.g., Freon 11" with Freon 12, or Freon 12" with Freon 114." For example, dichlorodifluoromethane, which has a Vapor pressure of about 70 pounds per square inch gaugeand 1,2dlCiiiO1O 1,1,2,2=tetrafluore-et nane (Freon 114"), with a vapor pressure of about 13 pounds per sqtiare inch gauge at 70 F., may be mixed in various proportions to form a propellant having an intermediate vapor pressure which is well suited for use in relatively low pressure containers.
it is most desirable that the vapor pressure of the propellant employed shall itself be Between about 25 and 65 pounds per square inch gauge at 70 F., arid prefer bly between about 30 and 40 pounds per square inch gauge at that temperature. A one-component propellant defined for use in the composition was found to give a composition with gauge pressures in the range of 55 to 65 pounds per square inch at 70 R, which are usable safely with metal containers. The two-component propellants, such as equal weight mixtures of "Freon 12 and Freon 11, were found to give gauge pressures in the range of 20 to 40 pounds per square inch at 70 R, which are usable safely with specially reinforced glass containers.
it is usually destirable to keep the gas pressure as low as possible, within the. limits imposed by the desired specific gravity of the propellant, in order to enable simple containers to be used safely and to prevent too high a pressure causing too wide a dispersal of the powder aerosol. When stronger containers, for example of stairs less steel, can be used and the active solid medicament is intended for pulmonary ingestion, it is advantageous to use a propellant with a gauge pressure of between 40 and 50 pounds per square inch; this allows complete aerosolization before the stream reaches the back of the throat. Since the powder is already present in the composition dispersed in the desired particle size, there is no need for further breakup action in the valve or applicator, so valves of simple construction may be used, and there is no need to provide special nozzles and expansion chambers, as is usually required when dispensing materials surface coating, which may even be a mono-molecular film or layer, on the finely-divided powder which prevents the particles from agglomerating either while dispersed in the propellant or when in the valve of the container.
. After an extensive investigation employing many surface-active agents, we have discovered that particular agents or combinations of them are required to give desirable results. During this investigation it was found unexpectedly that a number of surface-active agents providedv poor suspensions and failed to prevent agglomeration.
The liquid, non-ionic, surface-active agent employed should have an hydrophile-lipophile balance (HLB) ratio of less than 10. The HLB ratio is an empirical number which provides a guide to the surface-active properties of a surface-active agent. The lower the HLB ratio, the more lipophilic is the agent, and conversely, the higher the HLB ratio, the more hydrophiiic is the agent. The HLB ratio is well known and understood by the colloid chemist and its method of determination is described by W. C. Grifiin in the Journal of the Society of Cosmetic Chemists, vol. 1, No. 5, pages 311-326 (1949). Preferably the surface-active agent employed should have an HLB ratio of about 1 to 5. It is possible to employ surface-active agents which themselves do not possess an HLB ratio within these ranges, providing they are used in conjunction with other surface-active agents which have an HLB ratio which will provide a mixture having an HLB ratio within the prescribed range.
Surface-active agents which are solids at room temperature have been tried but appear to be unacceptable generally due to clogging of the valve and adapter orifices .on delivery. Lubricants for the valve, such as calcium stearate, which is without surfactant properties, were not found to be satisfactory, because they do not help to keep the powdered medicament uniformly dispersed in the pro pellant.
Those surface-active agents which are soluble or dispersible in the propellant are effective. The more propellant-soluble surface-active agents are the most effective.
For medicinal use it is also important that the surfaceactive agent should be non-irritating and non-toxic.
We have found that among the liquid non-ionic surfaceactive agents which may be employed in our compositions are the esters or partial esters of fatty acids containing from 6 to 22 carbon atoms, such as caproic, octoic, lauric, palmitic, stearic, linoleic, linolenic, eleostearic and oleic acids with an aliphatic polyhydric alcohol or its cyclic anhydride such as, for example, ethylene glycol, glycerol, erythritol, arabitol, mannitol, sorbitol, the hexitol anhydrides derived from sorbitol (the sorbitan esters sold under the trademark Spans") and the polyoxyethylene and polyoxypropylene derivatives of these esters. Mixed esters, such as mixed or natural glycerides may be employed. The preferred surface-active agents are the oleates of sorbitan, e.g., those sold under the trademarks Arlacel C (Sorbitan sesquioleate), Span 80 (sorbitan monooleate) and Span 85 (sorbitan trioleate).
Specific examples of other surface-active agents which may be employed are Sorbitan monolaurate V Polyoxyethylene sorbitol tetraoleate Polyoxyethylene sorbitol pentaoleate Indicative of the specificity of the surface-active agent in the compositions of the invention, there is reported below the results obtained with surface-active agents falling outside of the scope of the present invention and certain lubricants. These results are based upon tests employing the surface-active agent or lubricant in a concentration of 0.5% with a suspension of 0.5% of hydrocortisone acetate in a Freon mixture consisting of 30% Freon 11 and 70% of a mixture (Freon W) containing 61.5% Freon 114 and 38.5% Freon l2. Hydrocortisone acetate was used because it is one of the more easily suspended materials.
Compound Tested Results Paraffin Wax Stearic Acid Starry] Alcohol (solid). Beeswax Petrolatum Oleyl Alcohol (liquid) Pol yet hylene Glycol 300 Mineral Oil lsopropyl in yrist-nte Deposits as a solid in the adapter leading from the discharge valve and impairs delivery. Non- ,hornogeneous suspension. Lubricates valve.
Same as for paratlin wax.
. Same as for paraflin wax.
MYRJ 45" (Polyoxyethylene Very good suspension, elumpy, stearate). sticks to container, breaks very rapidly, lubrieates valve. Bi-i" (Poiyoxyctliylenelauryl Very poor suspension, clumpy,
alcohol). lubricntes valve. Tween 81 (Poiyoxyethylene Very poor suspension, elumpy,
sorbltnn mono-oleate). lubricates valve.
We have further discovered that in the case of compositions of the invention employing certain finely-divided powders there is a tendency to form a layer of powder at the surface of the propellant in the container and that these layers tend to deposit or cake" powdered material on the container walls above the liquid level. This has been found to occur only with those powders which have a specific gravity less than that of the propellant.
This tendency to deposit or cake out" is a serious disadvantage in that (1) such powder deposited on the container walls is not dispensed from the container, (2) the dose delivered is not correct and becomes progressively less as the amount left in the container becomes smaller and (3) in a transparent container the appearance of the product is impaired. The greater the difference in specific gravity between the powder and the propellant, the more pronounced in this tendency. By means of the present invention, it is possible to overcome these drawbacks and to provide more stable, uniform, attractive and satisfactory aerosol-producing compositions.
In some cases the undesirable deposition or caking which results where the specific gravity of the finely divided powder is substantially less than that of the propellant can be overcome by lowering the specific gravity of the liquid phase, for example by using a propellant of lower specific gravity, such as butane, or by increasing the specific gravity of the solid active powder component, for example in the case of phenylephrine by using the bitartrate salt instead of hydrochloride. In many cases, however, it is not possible to find a suitable alternative form of the active material. In such cases we have discovered, surprisingly, that the introduction of a sufficient quantity of an additional auxiliary finely divided solid of density greater than that of the liquid phase, will prevent the surface spread of lighter powders, thus avoiding caking out and the associated, above-mentioned drawbacks.
The nature of such an auxiliary solid may be of any chemical type, provided that it is compatible with the other ingredients and insoluble in the propellant. For example, we may use an inorganic compound such as sodium sulfate, calcium chloride or sodium chloride. We may also use an organic material such as powdered lactose, sucrose, epinephrine bitartrate, neomycin sulfate, or graphite. The auxiliary solid, when used in medicinal and cosmetic preparations, should be non-toxic and nonirritant. In all cases it should be without deleterious effect on the properties of the dispensed product or on the user. The particle size of the auxiliary solid should pp in this suitable for inhalation therapy.
.p =sp. gr. of auxiliary solid Pp=SP. gr. of propellant =sp. gr. of total powder constituents (auxiliary solid and active constituent) =sp. gr. of active constituent a=wt. of auxiliary solids p=wt. of propellant q='wt. of total powder constituents u=wt. of active constituent It is apparent that q=u plus a (1) To prevent surface deposit or caking the fol-lowing condition must exist:
p minus pp must not be less than zero (2) This condition is satisfied when:
PU is equal to or greater than pp (3) thus when q equals 11, equals zero. less than [312, the following exists:
u-l-a Pu PA But when p is I For a theoretical minimum, condition 2 becomes:
[7Q minus PP=ZCIO or p =p information to Equation 4, then:
( una -Px+ -Pu P thus:
uxin.
In terms of the above defined symbols, when P0 is equal to or greater than pp, a satisfactory composition is obtained whereby no surface deposit or caking of powder is obtained without the employment of an auxiliary solid or powder. When p is less than Pp, the minimum amount of auxiliary solid required to prevent deposit of solid from the composition, is expressed by Equation above. We
have found that satisfactory results may be obtained when up to about ten times the minimum is employed, but we prefer to employ between a and three times a The compositions of the invention may-be used to apply measured amounts of aerosolized solid medicaments into body cavities such as the throat or nose. They also provide a means of producing aerosolized medicaments Inhalation therapy is prompt through the intimate contact with the blood through the alveolar membrance. It also enablm drugs to act directly on respiratory sites without engendering undesirable systemic effects as happens often When drugs are administered by other routes. With very volatile substances inhalation approaches intravenous therapy in rapidity of. action. It willoften avoid the necessity of parenteral injections.- Previously aerosols for this purpose have been prepared by nebulizing aqueous solutions,
for example penicillin solutions in the treatment of pneu- 8 monia. Suspensions in oil have'been suggested in the treatment of bronchial asthma, but this is 'now widely condemned by the medical profession.
In producing the compositions and packages of the invention, a container equipped with a valve is filled with a propellant containing the finely-divided powder in suspension. A container may first be charged with a weighed amount of dry powder which has been ground to a predetermined particle size, or in a slurry of powder in the cooled liquid propellant. Alternatively and preferably, the powder and the surface-active agent may be triturated or homogenized first into a uniform paste, for instance, by a pestle and mortar. This paste is then dispersed in the cooled liquefied propellant. This procedure fosters uniform wetting of the powder particles. A container may also be filled by introducing powder and propellant by the normal cold filling method, or a slurry of the powder in that component of the propellant which boils above room temperature may be placed in the container, the valve sealed in place, and the balance of the propellant may be introduced by pressure filling through the valve nozzle. On operating the valve, the powder will be dispensed in a stream of propellant, which will vaporize providing an aerosol of dry powder. Throughout the preparation of the product care is desirably exercised to minimize the absorption of moisture where the powder is water-soluble. This may be accomplished by operat-' .ing in a dehumidified atmosphere using only dry materials and equipment.
When it is necessary to employ an auxiliary solid or powder to prevent surface deposit or caking, it is desirably introduced into the composition at the time that powdered of the appended claims. In the examples which follow,
the process described above was employed. In the examples which follow and throughout the specification, the quantities of material are expressed in terms of percentages by weight of the total composition, unless otherwise specified. The range of particle size specified in each example is that existing at the time of formulation. Where a constituent is described as micronized, it comprises 90% by weight of particles having a particle size range of between 1 and 5 microns. Examples 20 through 30 illustrate compositions in accordance with the invention employing an auxiliary solid to prevent surface deposit or caking.
Example 1 Percent Hydrocortisone acetate, crystalline (more than 90% by weight within the particle size range of l to 5 microns) 3.0 Span 85 (sorbitan trioleate) 1.0 Freon l1 (trichloromonofluoromethane) 30.0 Freon 114 (dichlorotetrafiuoroethane) 41.0 Freon 12 (dichlorodifiuoromethane) 25.0
Example 2 Gm. Trypsin, amorphous (more than 90% by weight within the particle size range of l to 10microns) 0.10
Span (sorbitan trioleate) 0.05 Propellant A 10.00
Example 3 Percent Pre dnisolone acetate, crystalline (more than 90% by weight within the particle size range of l to 5 microns) 0.5 Span 85 (sorbitan trioleate) 0.5 Propellant B 99.0
:7 Prcpellant B consists of:
Freon 11" (trichloromoncfiuoromethane) 10.0 Freon 114 (dichlorotetrafluorcethane) 50.4 Freon 12" (dichlorctetrafluoroethanc) 31.6 Butane a; 8.0
Example 4 ACTH (adrenocorticotropin) (amorphous) (l USP units/mg.) (more than 90% by weight within the particle size range, of 1 to 20 micron's) N 1.00
Span 85 ('sorbitan trioleate)" 0.25 Freon'l'l (trichlorornonofluoromethane) 5.00 Freon (as d'efined'in Example 2) 93.75
Example *5 v v Percent ACTH (Adrenocorticotropin) (amorphous) USP units/mg.) (more than 90% by weight within the particle. size range .of l. to :20
microns) 0.25
Span 85" (sorbit-an trioleate) 0.25 Freon W (as defined in EXampIe'Z) 99.50
Insulin, amorphous (more than 90% by weight I within the particle size range of 1 to 5 microns) 0.25 Span 85 (sorbitan trioleate) 0.25 Freon W (as defined in Example 2) 99.50
' Example 7 Epinephrine, crystalline (free base) (more than 90% by weight within the particle size range of 1 to 5 microns 0.28 Span 85 (sorbitan. trioleate) 0.25 Freon 11 (trichlorornonofluorometha-ne) 5.00
. Freon W (as defined in Example 2) 94.47
Example 8 Epinephrine bitartrate, crystalline (more than 90% by weight withinthe particle size range of 1 to 5 microns) 0.50 Span 85(sorbitan trioleate) 0.50 Freon 11"'(trichloromonofluoromethane) 49.50 Freon '12 (dichlorodifluoromethane) .l- 49.50
' 10 Example 9 Isopropylarterenol hydrochloride, crystalline (more than 90% by weight within the particle size range of l to 5 microns) 0.25 Span (sorbitan trioleate) 0.25 Freonll (trichlorornonofluoromethane) 49.75 Freon l2 (dichlorodifiuorcmethane) 49.75
Example 10 Phenylephrine hydrochloride, crystal-line (more than by weight within the particle size range of l to 25 microns) 0.25 Ncomycin sulfate 0.11 Hydrowrtisone 0.04 Span S5" (sorbitan trioleate) 0.25 Freon ll (trichloromonofiuoromethane) 49.675 Freon l2 (dichlorodifluorornethane) 49.675
Example 11 Neomycin sulfate, crystalline (more than 90% by weight within the particle size range of l to 25 microns) 0.50 "Span'SS (sorbita-n trioleate) 0.25 Freon ll (trichloromonofluorornethane) 4.75 Freon W (as defined lay-Example 2) 94.50
Example 12 Hydrocortisene acetate, crystalline (more than 90% by weight within the particle size range 'of l to 5 microns) 0.50
Surfactant 6-1087 (polyoxyethylene sorbitol hexaoleate) a, 0.50 Propcllant C 99.00
(Propellant C consists of: Freon 11 tn'chlorornoncflu'oromethane) 30.00% and Freon W (as defined in Example 2) 70.00%.)
Example 13 Percent Hydrocortisone acetate, crystalline (more than 90% by weight within the particle size range of 1 to 5 microns) 0.50 Arlacel C (sorbitan sesquioleate) 0.50 Propellant C (as defined by Example 12) 99.00
Example 14 Hydrocortisone acetate, crystalline (more than 90% by weight within the particle size range of 1 to 5 microns) 0.50 Span 80 (sorbitan monoleate) 0.50 Propellan-t- C (as defined-by Example 12) 99.00
Example 15 Hydrocortisone acetate, crystalline (more than 90% by weight within the particle size range of 1 to 5 microns) 0.50 Span S5 (sorbitan trioleate) 0.50 Propellant C-(as defined by Example 12) 99.00
Narcotine, crystalline (more than 90% by weight within the particle size range of 1 to microns) 10.00 Span 85 (sorbitan trioleate) 1.00 Freon W (as defined by Example 2) 89.00
100.00 Example 17 "Dilaudid, crystalline (dihydrornorphinone hydrochloride) (more than 90% by weight within the particle size range of 1 to 5 microns) 0.5 Span 85 (sorbitan trioleate) 1.0 Freon 11 (trichloromonofiuoromethane) 30.0 Freon W" (as defined by Example 2) 68.5
1000 Example 18 Iron oxide (jewelers rouge) (more than 90% by weight within the particle size range of 1 to 20 microns) 1.0 Span 80 (sorbitan monooleate) 0.25 Freon l2 (dichlorodifiuoromethane) 98.75
This composition is useful for polishing optical components.
Example 19 Percent Hydrocortisone acetate, crystalline (more than 90% 'by weight within the particle size range of 1 to 5 microns) 0.5 Olive oil 0.5 Freon 11 30.0 Freon W (as defined by Example 2) 69.0
100.0 Example 20 .Phenylephrine hydrochloride (crystalline), micronized 0.25 Phenylpropanolamine hydrochloride (crystalline), micronized 0.50 'Neomycin sulfate (crystalline), micronized 0.10 Hydrocortisone (crystalline), micronized 0.04 Sodium sulfate (anhydrous), micronizcd 0.35 Span 85" (sorbitan trioleate) 0.80 Prd'pellant S 97.96
v 100.00 Propellant S consists of:
Freon l2 (dichlorodifluoromethane) 27 Freon 11" (trichloromonofluoromethane) 30 Freon 114 (dichlorotetrafluoroethane) 43 Example 21 Percent Phenylephrine hydrochloride (crystalline), micronized 0.25 qlfleomycin sulfate (crystalline), micronized 0.10 Hydrocortisone (crystalline), micronized 0.04 Calcium chloride, micronized 0.10 Span 85 (sorbitan trioleate) 0.50 Propellant S (as defined by Example 20) 99.01
' 100.00 I Example 22 Phenylephrine hydrochloride (crystalline), micronized I 0.25 Sodium chloride (crystalline), powdered 0.50 Span 85" (sorbitan trioleate) 0.75
Propel-lam S (as defined in Example 20) 12 Example 23' Phenylephrine hydrochloride (crystalline), micronized 0.25 Epinephrine bitartrate (crystalline), micromzed 0.75 Span (sorbitan trioleate) 1.0 Propellan-t S (as defined in Example 20) 98.0
100.00 Example 24 Phenylephn'ne hydrochloride (crystalline), micronized 0.25 Sucrose (crystaline), powdered 0.50 Span 85 (sorbitan trioleate) 0.75 Propellant S (as defined in Example 20) 98.5
Example 25 Phcnylephrine hydrochloride (crystalline), micronized 1.0 Neomycin sulfate (crystalline), micronized 3.0 Span 85 (sorbitan trioleate) 1.0 Propellant S (as defined by Example 20) 95.0
100.0 Example 26 Phenylephrine hydrochloride (crystalline), mi-
eronized 0.25 Graphite powder 0.25 Span 85" (sorbitan trioleate) 0.50 Propellant S (as defined by Example 20) 99.0
100.00 Example 27 Hydrocortisone acetate (crytalline), micronized 0.88 Sodium sulfate (anhydrous), micronized 0.88 Span 85 (sorbitan trioleate) 1.00 Propellant 8-2 97.24
Q 100.00 Propellant S-2 consists of:
Freon 12" (dichlorodifluoromethane) 50 Freon 11 (trichloromonofiuoromethane) 25 Freon 114 (dichlorotetrafluoroethane) 25 Example 28 Phenylephrine hydrochloride (crystalline), mi-
cronized 0.25 Lactrose, powdered 0.50 Span 85 (sorbitan trioleate) 0.75 Propellant S (-as defined by Example 20) 98.5
100.00 Example 29 Phenylephrine hydrochloride (crystalline), mi-
cronized 0.25
Neomycin sulfate (crystalline), micronized 0.08
Span 85 (sorbitan trioleate) 0.50 Sodium sulfate AR, micronized 0.10 Propellant X 99.07
100.00 Propellant X consists of:
Freon 12 (dichlorodifluoromethane) 30 Freon 11 (trichloromonofiuoromethane) 30 Freon 114 (dichlorotetrafluoroethane) 40 Example 30 Phenylephn'ne hydrochloride (c ystalline), mi-
cronized 0.25 Neomycin sulfate (crystalline), micronized 0.08 Thenylpy'ramine hydrochloride (crystalline)," micronized 0.20
100.00 15 Sodium sulfate (crystalline), micronized 0.15
Span 85 (sorbitan trioleate) 0.70 Propellant X (as defined by Example 29) 98.62
' 100.00 Example 31 Isoproterenol sulfate, crystalline, micronized 0.15 Span 85 (sorbitan trioleate) 0.50 Freon 113 (trichlorotrifiuoroethane) 0.95 Freon 11 (trichloromonofiuoromethane) 24.60 Freon 114 (dichlorotetrafluoroethane) 24.60 Freon 12 (dichlorodifiuoromethane) 49.20
' 100.00 Example 32 Phenylpropanolamine hydrochloride, crystalline,
micronized 0.49 Phenylephrine hydrochloride, crystalline, mi-
cronized 0.35 Neomycin sulfate, crystalline, micronized 0.10 Hydrocortisone, crystalline, micronized 0.04 Sodium sulfate, crystalline (anhydrous), mi-
cronized 0.35 Span 85" 1.00 Freon 113? 1.00 .Freon 11 29.03 *Freon 12 29.03 .Freon 114 38.71
100.00 Example 33 'Phenylephrine hydrochloride, crystalline, mi-
cronized 0.25 Phenylpropanolamine hydrochloride, crystalline,
micronized 0.50 Neomycin sulfate, crystalline, micronized 0.08 Methapyrilene hydrochloride, crystalline, micronized I V 0.10 Sodium sulfate, crystalline, micronized 0.35 fSpan 85 1.00 Freon 113 1.00 Freon 11 29.01 .Freonll lf 38.70 Freon 12 29.01
. Example 34 Crystalline glucagon, micronized 0.156 "Span 85- 0.468 Propellant S" (as defined by Example 20) 99.376
, Example 35 Anhydrous cyanocobalamin, crystalline, micronized 0.039 Span 85 0.25 Propellant S (as defined by Example 20) 99.711
Example 36 I Chlorotetracycline hydrochloride, crystalline, mi-
cronized 0.5 Lactose 0.5 "Span 85 "Propellant S" (as defined by Example 20) 98.0.
Example 37 Adrenochrome, crystalline, micronized 1.785 Span 85 Propellant S" (as defined by Example 20) 97.215
14 Example 38 Phenylephrine hydrochloride, crystalline, mi-
cronized 0.253 Neomycin sulfate, crystalline, micronized 0.080 Methapyrilene hydrochloride, crystalline, mi-
cronized 0.198 Anhydrous sodium sulfate, crystalline, micronized 0.150 Span 1.00 Propellant X (as defined by Example 29) 98.319
The terms and expressions which we have employed are used as terms of description and not of limitation, and we have no intention, in the use of such terms and expressions, of excluding any equivalents of the features shown and described or portions thereof, but recognize that various modifications are possible within the scope of the invention claimed.
What is claimed is:
1. A self-propelling, powder dispensing composition capable of producing a useful substance in aerosol form comprising between about 0.01% and 20% by weight of a finely-divided powder of a particle size less than about microns suspended in a liquefied propellant having a vapor pressure of at least about 13 lbs. per square inch gauge at 70 F., and between about 0.1 and 20% by Weight of a liquid, non-ionic surface-active agent having a hydrophile-lipophile balance ratio of less than about 10 and being soluble in said liquefied propellant; said finelydivided powder being substantially insoluble in the mixture of propellant and surface active agent; and when said finely-divided powder is water-soluble, said composition shall contain not more than about 300 parts per million of moisture.
2. A self-propelling, powder dispensing composition as defined by claim 1, wherein the powder has a substantially uniform particle size of less than about 25 microns.
3. A self-propelling, powder dispensing composition as defined by claim 1, wherein the surface active'agent has a hydrophile-lipophile balance ratio of between 1 and 5.
4. A self-propelling, powder dispensing composition as defined in claim 1, wherein the finely-divided powder shall constitute between about 0.05% and 10% by weight and the liquid, non-ionic surface-active agent between about 0.1% and 5% by weight of the total composition.
5. A self-propelling, powder dispensing composition as defined by claim 4, wherein the surface active agent is an ester of a polyhydroxy compound. 1
6. A self-propelling, powder dispensing composition as defined by claim 4, wherein the surface active agent is a fatty acid ester of sorbitan.
7. A self-propelling, powder dispensing composition as defined by claim 4, wherein the surface active agent is an unsaturated fatty acid ester of sorbitan.
8. A self-propelling, powder dispensing composition as defined by claim 7 wherein the surface active agent is an oleic acid ester of sorbitan.
9. A self-propelling, powder dispensing composition as defined by claim 8 wherein the finely-divided powder comprises a member selected from the class consisting of prednisalone and its esters.
10. A self-propelling, powder dispensing composition as defined by claim 8 wherein the finely-divided powder comprises a member selected from the class consisting of epinephrine and its salts.
11. A self-propelling, powder dispensing composition as defined by claim 8 wherein the finely-divided powder comprises a salt of isoproterenol.
12. A self-propelling, powder dispensing composition as defined by claim 8 wherein the finely-divided powder comprises isoproterenol sulfate.
13. A self-propelling, powder dispensing composition as defined by claim 8 wherein the finely-divided powder comprises isoproterenol hydrochloride.
14. A self-propelling, powder dispensing composition as defined by claim 8 wherein the finely-divided powder comprises a mixture of phenylephrine hydrochloride, phenylpropanolamine hydrochloride, and methapyrilene hydrochloride.
15. A self-propelling, powder dispensing composition as defined in claim 8 wherein the finely-divided powder comprises a mixture of phenylpropanolamine hydrochloride, phenylephrine hydrochloride, neomycin sulfate and hydrocortisone.
16. A self-propelling, powder dispensing composition as defined by claim 8 wherein the finely-divided powder cornprises glucagon.
17. A self-propelling, powder dispensing composition as defined by claim 8 wherein the finely-divided powder comprises cyanocobalamin.
18. A self-propelling, powder dispensing composition as defined by claim 8 wherein the finely divided powder comprises chlorotetracycline hydrochloride.
1?. A self-propelling, powder dispensing composition as defined by claim 8 wherein the finely-divided powder comprises adrenochrome.
20. A self-propelling, powder dispensing pharmaceutical composition capable of providing a medicament in aerosol form suitable for inhalation therapy, comprising a liquefied non-toxic propellant having a vapor pressure of at least about 13 lbs. per square inch gauge at 70 F., between about 0.01% and 20% by weight of a finelydivided therapeutically active powdered medicament of substantially uniform particle size of less than about 100 microns suspended in said propellant, and between about 0.1% and 20% by weight of a liquid non-toxic non-ionic surface active agent having a hydrophile-lipophile balance ratio of less than about 10 and being soluble in said liquefied propellant; said finely-divided powder being substantially insoluble in the mixture of propellant and surface active agent; and when said finely-divided powder is watersoluble, said composition shall contain not more than about 300 parts per million of moisture.
21. A self-propelling, powder dispensing composition capable of producing a useful substance in aerosol form comprising a composition as defined in claim 1, wherein the specific gravity of the finely divided powder is at least as great as that of the liquefied propellant.
22. A self-propelling, powder dispensing composition capable of producing a useful substance in aerosol form comprising a composition as defined by claim 1 having "11 units by weight of a useful substance of specific gravity as a finely-divided powder and aunits by weight of an auxiliary solid substance of specific gravity p in powdered form suspended in a liquid of specific gravity pp wherein the minimum value of is expressed as follows:
a u n u 23. A self-propelling, powder dispensing composition capable of producing a useful substance in aerosol form according to claim 22, wherein the amount of :1 lies between the value of a f and 10 times a 24. A self-propelling, powder dispensing composition capable of producing a useful substance in aerosol form according to claim 22, wherein the amount of a lies between the valve of a and 3 times a 25. A self-propelling, powder dispensing composition capable of producing a useful substance in aerosol form according to claim 24, wherein the useful substance is a medicament and the auxiliary solid is a non-toxic powdered substance of particle size less than 25 microns.
26. A self-propelling powder dispensing composition capable of producing a useful substance in aerosol form according to claim 22', wherein the auxiliary solid is sodium sulfate.
27. A self-propelling, powder dispensing composition capable of producing a useful substance in aerosol form according to claim 22, wherein the auxiliary solid is calcium chloride.
28. A self-propelling, powder dispensing composition capable of producing a useful substance in aerosol form according to claim 22, wherein the auxiliary solid is lactose.
29. A self-propelling, powder dispensing composition capable of producing a useful substance in aerosol form according to claim 22, wherein the auxiliary solid is sucrose.
30. A package comprising a pressure-tight container having a valve-controlled opening and containing alpharmaceutical composition capable of providing a measured dose of medicament in aerosol form suitable for inhalation therapy, comprising a composition as defined by claim 20 31. A self-propelling, powder dispensing composition as defined by claim 8 wherein the finely-divided powder comprises adrenocorticotropin.
References Cited in the file of this patent UNITED STATES PATENTS 2,594,296 Dautrebande Apr. 29, 1952 2,728,495 Eaton Dec. 27, 1955 2,782,975 Bird Feb. 26, 1957 2,959,325 Beard Nov. 8, 1960 OTHER REFERENCES Atlas Spans and Tweens, Atlas Powder Co.,
.mington, Del., 1942, pages 7, 8, 9 and 11.
Journal of The Society of Cosmetic Chemists (I.S.C.C.), vol. 7, No. 4, July 1956, pages 352 and 353.
Drug and Cosmetic Industry, vol. 79, No. 3, September 1956, pages 328 and 329.
Beard: Powder Aerosols, ties, vol. 31, No. 1, January 169.
Merck Index, 6th edition, Merck & Co., Rahway, N.J., 1952, pages 388, 389, 512, 559 and 560.
Becher: Principles of Emulsion Technology, Reinhold Publ. Co., New York (1955), pages 106-7.
Schwartz et al.: Surface Active Agents, Interscience Publ. Inc., New York, vol. 1 (1949), pages 324, 328.
Atlas Guide to Use of Sorbitol and Surfactants in Cosmetics, November 1956, pages 19 and 21.
Shephard: Proceedings of Scientific Sec. of Toilet Goods Assn., No. 22, December 1954, pages 30-31.
Soap and Chemical Special- 1955, pages 139, 141 and UNITED STATES PATENT OFFICE CERTIFICATION OF CORRECTION fauna No 3,014,844 December 26, 1961 Charles G, Thiel et al.
It is hereby certified that error appears in the abo' ent requiring correction and that the said Letters Patent corrected below.
Column 2, line 46, for "a" read the line 47, before "mixture" insert agent column 3, line 68, for "usch" read such column 4, line 12, for "aand" read and column 5, line 21, for "vol." read Vol. column 6, line 56, after "of" insert the column 7, line 67, for "membrance" read membrane column 9, line 19, for "dichlorotetrafluoroethane" read dichlorodifluoromethane column 9, lines 25, 47, 57, and 67,colmma 10, lines 3, 12, 23, 33, 58, and 67, column 11, line 3, l0, 19, 40, and 68, column 12, lines 3, l0, 18, 27, 36, 47, 56, and 69, column 13, lines 6, 14, 32, 4B, 54, 62, and 70, and column 14, line 3, the word "Percent" should be inserted as a heading in the amounts set forth in the right-hand columns, each occurrence; column 12, line 50, for
"Lactrose" read Lactose column 14, line 43, column 15, lines 7 and 42,inf each occurrence, read by column 16, line 3, for "valve" read value same column line 57, for "pages 324, 328" read pages 324 through 328 Signed and sealed this 24th day of April 1962.
(SEAL) Attest:
ESTON G. JOHNSON DAVID L. LADD Attesting Officer Commissioner of Patents UNITED STATES PATENT OFFICE CERTIFICATION OF CORRECTION Patent No. 3,014,844 December 26, 1961 Charles G. Thiel et a1.
It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.
Column 2, line 46, for "a" read the line 47, before "mixture" insert agent column 3, line 68, for "usch" read such column 4, line 12, for "aand" read and column 5, line 21, for "vol." read Vol. column 6, line 56, after "of" insert the column 7, line 67, for "membrance" read membrane column 9, line 19, for "dichlorotetrafluoroethane" read dichlorodifluoromethane column 9, lines 25, 47, 57, and 67, column 10, lines 3, 12, 23, 33, 58, and 67, column 11, line 3, 1O, 19, 40, and 68, column 12, lines 3, 1O, 18, 27, 36, 47, 56, and 69, column 13, lines 6, 14, 32,
48, 54, 62, and 70, and column 14, line 3, the word "Percent" should be inserted as a heading in the amounts set forth in the right-hand columns, each occurrence; column 12, line 50, for
I "Lactrose" read Lactose column 14, line 43, column 15, lines 7 and 42, "in," each occurrence, read by column 16, line 3, for "valve" read value same column line 57, for
"pages 324, 328" read pages 324 through 328 Signed and sealed this 24th day of April 1962.
(SEAL) Attest:
ESTON G. JOHNSON DAVID L. LADD Attesting Officer Commissioner of Patents UNITED STATES PATENT OFFICE CERTIFICATION OF CORRECTION Patent No. 3, 14,844 December 26, 1961 Charles G, Thiel et a1.
It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below. I
Column 2, line 46, for "a" read the line 47, before "mixture" insert agent column 3, line 68, for "usch" read such column 4, line 12, for "aand" read and column 5, line 21, for "vol." read Vol. column 6, line 56, after "of" insert the column 7, line 67, for "membrance" read membrane column 9, line 19, for "dichlorotetrafluoroethane" read dichlorodifluoromethane column 9, lines 25, 47, 57, and 67, column 10, lines 3, 12, 23, 33, 58, and 67, column 11, line 3, 1O, 19, 40, and 68, column 12, lines 3, 1O, 18, 27, 36, 47, 56, and 69, column 13, lines 6, 14, 32, 48, 54, 62, and 70, and column 14, line 3, the word "Percent" should be inserted as a heading in the amounts set forth in the righthand columns, each occurrence; column l2, line 50, for
"Lactrose" read Lactose column 14, line 43, column 15, lines 7 and 42,"in," each occurrence, read by column 16, line 3, for "valve" read value same column line 57, for
"pages 324, 328" read pages 324 through 328 Signed and sealed this 24th day of April 1962.
(SEAL) Attest:
ESTON G. JOHNSON DAVID L. LADD Attesting Officer Commissioner of Patents
Claims (1)
1. A SELF-PROPELLING, POWEDER DISPENSING COMPOSITION CAPABLE OF PRODUCING A USEFUL SUBSTANCE IN AEROSOL FROM COMPRISING BETWEEN ABOUT 0.01% AND 20% BY WEIGHT OF A FINELY-DIVIDED POWDER OF A PARTICLE SIZE LESS THAN ABOUT 100 MICRONS SUSPENDED IN A LIQUEFIED PROPELLANT HAVING A VAPOR PRESSURE OF AT LEAST ABOUT 13 LBS. PER SQUARE INCH GAUGE AT 70*F., AND BETWEEN ABOUT 0.1 AND 20% BY WEIGHT OF A LIQUID, NON-IONIC SURFACE-ACTIVE AGENT HAVING A HYDROPHILE-LIPOPHILE BALANCE RATIO OF LESS THAN ABOUT 10 AND BEING SOLUBLE IN SAID LIQUEFIED PROPELLANT, SAID FINELYDIVIDED POWDER BEING SUBSTANTIALLY INSOLUBLE IN THE MIXTURE OF PROPELLANT AND SURFACE ACTIVE AGENT, AND WHEN SAID FINELY-DIVIDED POWDER IS WATER-SOLUBLE, SAID COMPOSITION SHALL CONTAIN NOT MORE THAN ABOUT 300 PARTS PER MILLION OF MOISTURE.
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
BE556587D BE556587A (en) | 1957-01-31 | 1957-04-30 | |
US706908A US3014844A (en) | 1957-01-31 | 1958-01-03 | Self-propelling powder dispensing compositions |
DER22567A DE1178975B (en) | 1957-01-31 | 1958-01-27 | Method of making an inhalant |
GB2644/58A GB837465A (en) | 1957-01-31 | 1958-01-27 | Self-propelling, powder-dispensing compositions |
FR756970A FR1228811A (en) | 1957-01-31 | 1958-01-29 | Self-propelling composition for powder distribution |
NL224547D NL224547A (en) | 1957-01-31 | 1958-01-31 | |
NL224547A NL106832C (en) | 1957-01-31 | 1958-01-31 |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US63735357A | 1957-01-31 | 1957-01-31 | |
US68001657A | 1957-08-23 | 1957-08-23 | |
US706908A US3014844A (en) | 1957-01-31 | 1958-01-03 | Self-propelling powder dispensing compositions |
Publications (1)
Publication Number | Publication Date |
---|---|
US3014844A true US3014844A (en) | 1961-12-26 |
Family
ID=22180422
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US706908A Expired - Lifetime US3014844A (en) | 1957-01-31 | 1958-01-03 | Self-propelling powder dispensing compositions |
Country Status (6)
Country | Link |
---|---|
US (1) | US3014844A (en) |
BE (1) | BE556587A (en) |
DE (1) | DE1178975B (en) |
FR (1) | FR1228811A (en) |
GB (1) | GB837465A (en) |
NL (2) | NL224547A (en) |
Cited By (100)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3076745A (en) * | 1958-11-17 | 1963-02-05 | Poultry Service And Res Corp | Antibiotic method for promoting poultry growth |
US3079299A (en) * | 1959-11-16 | 1963-02-26 | Gen Aerosol Corp | Self-propelling medicinal ointment composition containing polyethylene and method ofapplication |
US3088874A (en) * | 1960-05-23 | 1963-05-07 | Union Carbide Corp | Powder aerosol |
US3095355A (en) * | 1961-10-12 | 1963-06-25 | Revlon | Aerosol composition |
US3124505A (en) * | 1964-03-10 | Aerosol concentrates containing a sta- | ||
US3135658A (en) * | 1961-10-10 | 1964-06-02 | Merck & Co Inc | Non-aqueous oleaginous aerosol foam therapy of bovine mastitis |
US3155574A (en) * | 1962-05-24 | 1964-11-03 | Revlon | Aerosol composition |
US3155573A (en) * | 1958-05-06 | 1964-11-03 | Benger Lab Ltd | Inhalant composition and method of making same |
US3169095A (en) * | 1962-10-30 | 1965-02-09 | Rexall Drug Chemical | Self-propelling powder-dispensing compositions |
US3219533A (en) * | 1962-11-29 | 1965-11-23 | Merck & Co Inc | Aerosol solid medicament in propellant and low-level ethanol avoiding higher-level ethanol dispersed-solid reflocculation |
US3260408A (en) * | 1964-04-08 | 1966-07-12 | Bell & Howell Co | Method and means of dispersing particulate material in a stream of carrier fluid |
US3282791A (en) * | 1965-08-17 | 1966-11-01 | Merck & Co Inc | Inhalation aerosol suspension of anhydrous disodium dexamethasone phosphate, propellents, and sorbitan trioleate |
US3288681A (en) * | 1962-05-01 | 1966-11-29 | Lever Brothers Ltd | Anhydrous aluminum antiperspirant powder aerosol compositions and methods of preparation |
US3304230A (en) * | 1963-02-18 | 1967-02-14 | Revlon | Liquid aerosol propellant solutions of fatty acid salts of physiologically active amines |
US3345295A (en) * | 1963-02-13 | 1967-10-03 | Shulton Inc | Copper cleaning compositions |
US3402665A (en) * | 1966-08-15 | 1968-09-24 | Aeroprojects Inc | Nonpyrotechnic disseminator |
US3446892A (en) * | 1963-09-18 | 1969-05-27 | Whitmire Research Lab Inc | Immobilizing insects by sudden reduction of body temperature |
DE2320111A1 (en) * | 1972-04-20 | 1973-10-31 | Allen & Hanburys Ltd | SOLVATED, CRYSTALLINE, ANTI-INFLAMMATORY STEROIDS, METHODS FOR THEIR PRODUCTION AND AEROSOL FORMULATIONS CONTAINING THESE MATERIALS |
US3923971A (en) * | 1973-09-13 | 1975-12-02 | Alexandre Seilinger | Antiperspirant and deodorant composition containing lamellar substances |
US3968203A (en) * | 1965-10-01 | 1976-07-06 | Jerome G. Spitzer | Aerosol astringent composition |
US4010252A (en) * | 1974-12-19 | 1977-03-01 | Colgate-Palmolive Company | Antimicrobial compositions |
US4027007A (en) * | 1970-12-09 | 1977-05-31 | Colgate-Palmolive Company | Antiperspirants formulated with borax |
DE2703119A1 (en) * | 1976-01-30 | 1977-08-04 | Fisons Ltd | SODIUMCROMOGLYCAT WITH LESS THAN 5% WATER AND THIS COMPREHENSIVE PHARMACEUTICAL PREPARATIONS |
DE2831419A1 (en) * | 1977-07-19 | 1979-02-01 | Fisons Ltd | Aerosol compsn., pref. contg. fine medicament |
US4147766A (en) * | 1976-06-09 | 1979-04-03 | Armour Pharmaceutical Company | Macrospherical particles of anti-perspirants |
US4192766A (en) * | 1975-04-25 | 1980-03-11 | United Chemical Corporation | Composition for decreasing water resistance to movement |
US4352789A (en) * | 1980-03-17 | 1982-10-05 | Minnesota Mining And Manufacturing Company | Aerosol compositions containing finely divided solid materials |
EP0047122A3 (en) * | 1980-08-28 | 1983-01-26 | Eli Lilly And Company | Intranasal formulation |
US4411883A (en) * | 1973-02-05 | 1983-10-25 | Colgate-Palmolive Company | Antiperspirant |
US4450151A (en) * | 1978-08-21 | 1984-05-22 | Toyo Aerosol Industry Co., Ltd. | Powder aerosol composition |
JPS60252410A (en) * | 1984-04-25 | 1985-12-13 | イーライ・リリー・アンド・カンパニー | Slow-release nasal medicine and use |
US4605552A (en) * | 1983-07-20 | 1986-08-12 | Warner-Lambert Company | Calcium-antagonist compositions intended for inhalation and process for their manufacture |
EP0160501A3 (en) * | 1984-04-25 | 1986-12-30 | Eli Lilly And Company | Sustained release intranasal formulation and method of use thereof |
US5225183A (en) * | 1988-12-06 | 1993-07-06 | Riker Laboratories, Inc. | Medicinal aerosol formulations |
US5348730A (en) * | 1989-09-20 | 1994-09-20 | Minnesota Mining And Manufacturing Company | Method for preparing medicinal aerosol formulation containing coated medicament |
US5368842A (en) * | 1992-10-29 | 1994-11-29 | The Gillette Company | High efficacy aerosol antiperspirant composition |
US5439670A (en) * | 1989-11-28 | 1995-08-08 | Riker Laboratories, Inc. | Medicinal aerosol formulations |
US5653962A (en) * | 1991-12-12 | 1997-08-05 | Glaxo Group Limited | Aerosol formulations containing P134a and particulate medicaments |
US5658549A (en) * | 1991-12-12 | 1997-08-19 | Glaxo Group Limited | Aerosol formulations containing propellant 134a and fluticasone propionate |
US5674471A (en) * | 1991-12-12 | 1997-10-07 | Glaxo Group Limited | Aerosol formulations containing P134a and salbutamol |
US5674472A (en) * | 1991-12-12 | 1997-10-07 | Glaxo Group Limited | Canisters containing aerosol formulations containing P134a and fluticasone propionate |
US5736124A (en) * | 1991-12-12 | 1998-04-07 | Glaxo Group Limited | Aerosol formulations containing P134a and particulate medicament |
US5744123A (en) * | 1991-12-12 | 1998-04-28 | Glaxo Group Limited | Aerosol formulations containing P134a and particulate medicaments |
US5747445A (en) * | 1993-06-24 | 1998-05-05 | Astra Aktiebolag | Therapeutic preparation for inhalation |
US5756071A (en) * | 1992-06-03 | 1998-05-26 | Arrowdean Limited | Method for nasally administering aerosols of therapeutic agents to enhance penetration of the blood brain barrier |
US5766573A (en) * | 1988-12-06 | 1998-06-16 | Riker Laboratories, Inc. | Medicinal aerosol formulations |
US5776432A (en) * | 1990-10-18 | 1998-07-07 | Minnesota Mining And Manufacturing Company | Beclomethasone solution aerosol formulations |
US5817293A (en) * | 1991-12-12 | 1998-10-06 | Glaxo Group Limited | Canister containing aerosol formulations containing P134a and particulate medicaments |
US5830853A (en) * | 1994-06-23 | 1998-11-03 | Astra Aktiebolag | Systemic administration of a therapeutic preparation |
US5916540A (en) * | 1994-10-24 | 1999-06-29 | Glaxo Group Limited | Aerosol formulations containing P134A and/or P227 and particulate medicament |
US5922306A (en) * | 1991-12-12 | 1999-07-13 | Glaxo Group Limited | Aerosol formulations containing P134a and particulate medicament |
US5952008A (en) * | 1993-06-24 | 1999-09-14 | Ab Astra | Processes for preparing compositions for inhalation |
US6004574A (en) * | 1994-12-22 | 1999-12-21 | Astra Aktiebolag | Powder formulations containing melezitose as a diluent |
US6054488A (en) * | 1996-06-11 | 2000-04-25 | 3M Innovative Properties Company | Medicinal aerosol formulations of formoterol |
WO1999065460A3 (en) * | 1998-06-19 | 2000-04-27 | Baker Norton Pharma | Pressurized metered dose inhalers and pharmaceutical aerosol formulations comprising a beta-agonist |
US6290930B1 (en) | 1998-12-18 | 2001-09-18 | Baker Norton Pharmaceuticals, Inc. | Pharmaceutical solution aerosol formulations containing fluoroalkanes and budesonide |
US6306440B1 (en) | 1993-06-24 | 2001-10-23 | Astrazeneca Ab | Therapeutic preparation for inhalation |
US6309623B1 (en) | 1997-09-29 | 2001-10-30 | Inhale Therapeutic Systems, Inc. | Stabilized preparations for use in metered dose inhalers |
US20020010318A1 (en) * | 1997-10-03 | 2002-01-24 | Amgen, Inc. | Secretory leukocyte protease inhibitor dry powder pharmaceutical compositions |
US6433040B1 (en) | 1997-09-29 | 2002-08-13 | Inhale Therapeutic Systems, Inc. | Stabilized bioactive preparations and methods of use |
US6436902B1 (en) | 1994-12-22 | 2002-08-20 | Astrazeneca Ab | Therapeutic preparations for inhalation |
US6461591B1 (en) | 1997-02-05 | 2002-10-08 | Jago Research Ag | Medical aerosol formulations |
US6475467B1 (en) | 1998-08-04 | 2002-11-05 | Jago Research Ag | Medicinal aerosol formulations |
US6524557B1 (en) | 1994-12-22 | 2003-02-25 | Astrazeneca Ab | Aerosol formulations of peptides and proteins |
US6565885B1 (en) | 1997-09-29 | 2003-05-20 | Inhale Therapeutic Systems, Inc. | Methods of spray drying pharmaceutical compositions |
US6585958B1 (en) | 1998-07-24 | 2003-07-01 | Jago Research Ag | Medicinal aerosol formulations |
US6610653B1 (en) | 1994-06-23 | 2003-08-26 | Astrazeneca Ab | Therapeutic preparation for inhalation |
US6632456B1 (en) | 1993-06-24 | 2003-10-14 | Astrazeneca Ab | Compositions for inhalation |
US20030211972A1 (en) * | 1993-06-24 | 2003-11-13 | Astrazeneca Ab, A Sweden Corporation | Systemic administration of a therapeutic preparation |
US6743413B1 (en) | 1991-12-18 | 2004-06-01 | 3M Company | Suspension aerosol formulations |
US20040171550A1 (en) * | 1993-06-24 | 2004-09-02 | Astrazeneca Ab, A Swedish Corporation | Compositions for inhalation |
US20050031548A1 (en) * | 1990-02-03 | 2005-02-10 | Boehringer Ingelheim Kg | Suspension aerosol formulations of pharmaceutical products |
US6932962B1 (en) | 1994-12-22 | 2005-08-23 | Astrazeneca Ab | Aerosol drug formulations containing hydrofluoroalkanes and alkyl saccharides |
US6946117B1 (en) | 1997-09-29 | 2005-09-20 | Nektar Therapeutics | Stabilized preparations for use in nebulizers |
US7101534B1 (en) | 1991-12-18 | 2006-09-05 | 3M Innovative Properties Company | Suspension aerosol formulations |
US7105152B1 (en) | 1991-12-18 | 2006-09-12 | 3M Innovative Properties Company | Suspension aerosol formulations |
US7368102B2 (en) | 2001-12-19 | 2008-05-06 | Nektar Therapeutics | Pulmonary delivery of aminoglycosides |
EP1949891A1 (en) | 2004-10-12 | 2008-07-30 | Generics (UK) Limited | Process for the preparation of suspension aerosol formulations, wherein the particles are formed by precipitation inside an aerosol canister |
US7442388B2 (en) | 2000-05-10 | 2008-10-28 | Weers Jeffry G | Phospholipid-based powders for drug delivery |
US20080287451A1 (en) * | 2007-02-11 | 2008-11-20 | Cook Robert O | Method of therapeutic administration of DHE to enable rapid relief of migraine while minimizing side effect profile |
US7566445B1 (en) | 1996-08-01 | 2009-07-28 | Norton Healthcare Limited | Medicinal aerosols and methods of delivery thereof |
US20090191134A1 (en) * | 2006-06-12 | 2009-07-30 | Medispray Laboratoriespvt. Ltd. | Stable aerosol pharmaceutical formulations |
US7582284B2 (en) | 2002-04-17 | 2009-09-01 | Nektar Therapeutics | Particulate materials |
US20090297457A1 (en) * | 2004-10-12 | 2009-12-03 | Generics [Uk] Limited | Preparation Of Suspension Aerosol Formulations |
US7871598B1 (en) | 2000-05-10 | 2011-01-18 | Novartis Ag | Stable metal ion-lipid powdered pharmaceutical compositions for drug delivery and methods of use |
US8080236B2 (en) | 2002-04-17 | 2011-12-20 | Nektar Therapeutics Uk, Ltd | Particulate materials |
WO2012106382A1 (en) | 2011-01-31 | 2012-08-09 | Genoa Pharmaceuticals, Inc. | Aerosol pirfenidone and pyridone analog compounds and uses thereof |
US8246934B2 (en) | 1997-09-29 | 2012-08-21 | Novartis Ag | Respiratory dispersion for metered dose inhalers comprising perforated microstructures |
US8357696B2 (en) | 2005-05-18 | 2013-01-22 | Mpex Pharmaceuticals, Inc. | Aerosolized fluoroquinolones and uses thereof |
US8367734B1 (en) | 2005-08-11 | 2013-02-05 | Amphastar Pharmaceuticals Inc. | Stable epinephrine suspension formulation with high inhalation delivery efficiency |
US8404217B2 (en) | 2000-05-10 | 2013-03-26 | Novartis Ag | Formulation for pulmonary administration of antifungal agents, and associated methods of manufacture and use |
EP2594272A2 (en) | 2005-05-18 | 2013-05-22 | Mpex Pharmaceuticals, Inc. | Aerosolized fluoroquinolones and uses thereof |
US8629139B2 (en) | 2008-10-07 | 2014-01-14 | Mpex Pharmaceuticals, Inc. | Topical use of Levofloxacin for reducing lung inflammation |
US8815838B2 (en) | 2008-10-07 | 2014-08-26 | David C. Griffith | Aerosol fluoroquinolone formulations for improved pharmacokinetics |
US9700564B2 (en) | 2009-09-04 | 2017-07-11 | Horizon Orphan Llc | Use of aerosolized levofloxacin for treating cystic fibrosis |
US10028966B2 (en) | 2014-01-10 | 2018-07-24 | Avalyn Pharma Inc. | Aerosol pirfenidone and pyridone analog compounds and uses thereof |
EP3782604A1 (en) | 2013-07-31 | 2021-02-24 | Windward Pharma, Inc. | Aerosol tyrosine kinase inhibitor compounds and uses thereof |
WO2022240897A1 (en) | 2021-05-10 | 2022-11-17 | Sepelo Therapeutics, Llc | Pharmaceutical composition comprising delafloxacin for administration into the lung |
WO2023028364A1 (en) | 2021-08-27 | 2023-03-02 | Sepelo Therapeutics, Llc | Targeted compositions and uses therof |
US11633556B2 (en) | 2017-09-22 | 2023-04-25 | Imperial Tobacco Limited | Aerosolization using two aerosol generators |
Families Citing this family (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE1170909B (en) * | 1961-02-17 | 1964-05-27 | Specialties Dev Corp | Self-propelling mixture |
DE2804931A1 (en) * | 1978-02-06 | 1979-08-16 | Fresenius Chem Pharm Ind | METAL SULFADIAZINE IN FINE PARTICULAR FORM |
JPS59163313A (en) * | 1983-03-09 | 1984-09-14 | Teijin Ltd | Peptide hormone composition for nasal administration |
GB8828477D0 (en) | 1988-12-06 | 1989-01-05 | Riker Laboratories Inc | Medical aerosol formulations |
WO1990009781A1 (en) * | 1989-02-23 | 1990-09-07 | Rorer International (Holdings), Inc. | Therapeutic aerosol formulations |
HU205249B (en) * | 1990-11-09 | 1992-04-28 | Egyt Gyogyszervegyeszeti Gyar | Process for producing suspensive aerosole composition |
RU2054180C1 (en) * | 1991-08-21 | 1996-02-10 | Жирнов Олег Петрович (н/п) | Method and aerosol for treating respiratory virus infections |
GB0614621D0 (en) | 2006-07-24 | 2006-08-30 | 3M Innovative Properties Co | Metered dose dispensers |
GB0620700D0 (en) | 2006-10-19 | 2006-11-29 | 3M Innovative Properties Co | Metered dose valves and dispensers |
GB201118188D0 (en) | 2011-10-21 | 2011-12-07 | 3M Innovative Properties Co | Manufacture of medicinal aerosol canisters |
GB201210580D0 (en) | 2012-06-14 | 2012-08-01 | 3M Innovative Properties Co | Metered dose dispensing valve |
GB201221063D0 (en) | 2012-11-23 | 2013-01-09 | 3M Innovative Properties Co | Metered dose dispensing valve |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2594296A (en) * | 1948-06-24 | 1952-04-29 | Aerosol Corp | Lobeline aerosol dilating medicament |
US2728495A (en) * | 1951-04-19 | 1955-12-27 | Little Inc A | Liquid dispensing device and composition therefor |
US2782975A (en) * | 1955-04-20 | 1957-02-26 | American Cyanamid Co | Sprayable amorphous antibiotic composition, pressurized container with same, and method of preparing |
US2959325A (en) * | 1954-04-29 | 1960-11-08 | Risdon Mfg Co | Method and apparatus for dispensing dry powders |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2440915A (en) * | 1946-01-03 | 1948-05-04 | Roberts Mfg Co | Process for producing aerosols |
US2524590A (en) * | 1946-04-22 | 1950-10-03 | Carsten F Boe | Emulsion containing a liquefied propellant gas under pressure and method of spraying same |
GB764862A (en) * | 1953-02-16 | 1957-01-02 | Midland Silicones Ltd | An article for dispensing organosilicon compounds |
-
1957
- 1957-04-30 BE BE556587D patent/BE556587A/xx unknown
-
1958
- 1958-01-03 US US706908A patent/US3014844A/en not_active Expired - Lifetime
- 1958-01-27 DE DER22567A patent/DE1178975B/en active Pending
- 1958-01-27 GB GB2644/58A patent/GB837465A/en not_active Expired
- 1958-01-29 FR FR756970A patent/FR1228811A/en not_active Expired
- 1958-01-31 NL NL224547D patent/NL224547A/xx unknown
- 1958-01-31 NL NL224547A patent/NL106832C/xx active
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2594296A (en) * | 1948-06-24 | 1952-04-29 | Aerosol Corp | Lobeline aerosol dilating medicament |
US2728495A (en) * | 1951-04-19 | 1955-12-27 | Little Inc A | Liquid dispensing device and composition therefor |
US2959325A (en) * | 1954-04-29 | 1960-11-08 | Risdon Mfg Co | Method and apparatus for dispensing dry powders |
US2782975A (en) * | 1955-04-20 | 1957-02-26 | American Cyanamid Co | Sprayable amorphous antibiotic composition, pressurized container with same, and method of preparing |
Cited By (182)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3124505A (en) * | 1964-03-10 | Aerosol concentrates containing a sta- | ||
US3155573A (en) * | 1958-05-06 | 1964-11-03 | Benger Lab Ltd | Inhalant composition and method of making same |
US3076745A (en) * | 1958-11-17 | 1963-02-05 | Poultry Service And Res Corp | Antibiotic method for promoting poultry growth |
US3079299A (en) * | 1959-11-16 | 1963-02-26 | Gen Aerosol Corp | Self-propelling medicinal ointment composition containing polyethylene and method ofapplication |
US3088874A (en) * | 1960-05-23 | 1963-05-07 | Union Carbide Corp | Powder aerosol |
US3135658A (en) * | 1961-10-10 | 1964-06-02 | Merck & Co Inc | Non-aqueous oleaginous aerosol foam therapy of bovine mastitis |
US3095355A (en) * | 1961-10-12 | 1963-06-25 | Revlon | Aerosol composition |
US3288681A (en) * | 1962-05-01 | 1966-11-29 | Lever Brothers Ltd | Anhydrous aluminum antiperspirant powder aerosol compositions and methods of preparation |
US3155574A (en) * | 1962-05-24 | 1964-11-03 | Revlon | Aerosol composition |
US3169095A (en) * | 1962-10-30 | 1965-02-09 | Rexall Drug Chemical | Self-propelling powder-dispensing compositions |
US3219533A (en) * | 1962-11-29 | 1965-11-23 | Merck & Co Inc | Aerosol solid medicament in propellant and low-level ethanol avoiding higher-level ethanol dispersed-solid reflocculation |
US3345295A (en) * | 1963-02-13 | 1967-10-03 | Shulton Inc | Copper cleaning compositions |
US3304230A (en) * | 1963-02-18 | 1967-02-14 | Revlon | Liquid aerosol propellant solutions of fatty acid salts of physiologically active amines |
US3446892A (en) * | 1963-09-18 | 1969-05-27 | Whitmire Research Lab Inc | Immobilizing insects by sudden reduction of body temperature |
US3260408A (en) * | 1964-04-08 | 1966-07-12 | Bell & Howell Co | Method and means of dispersing particulate material in a stream of carrier fluid |
US3282791A (en) * | 1965-08-17 | 1966-11-01 | Merck & Co Inc | Inhalation aerosol suspension of anhydrous disodium dexamethasone phosphate, propellents, and sorbitan trioleate |
US3968203A (en) * | 1965-10-01 | 1976-07-06 | Jerome G. Spitzer | Aerosol astringent composition |
US3402665A (en) * | 1966-08-15 | 1968-09-24 | Aeroprojects Inc | Nonpyrotechnic disseminator |
US4027007A (en) * | 1970-12-09 | 1977-05-31 | Colgate-Palmolive Company | Antiperspirants formulated with borax |
DE2320111A1 (en) * | 1972-04-20 | 1973-10-31 | Allen & Hanburys Ltd | SOLVATED, CRYSTALLINE, ANTI-INFLAMMATORY STEROIDS, METHODS FOR THEIR PRODUCTION AND AEROSOL FORMULATIONS CONTAINING THESE MATERIALS |
US4411883A (en) * | 1973-02-05 | 1983-10-25 | Colgate-Palmolive Company | Antiperspirant |
US3923971A (en) * | 1973-09-13 | 1975-12-02 | Alexandre Seilinger | Antiperspirant and deodorant composition containing lamellar substances |
US4010252A (en) * | 1974-12-19 | 1977-03-01 | Colgate-Palmolive Company | Antimicrobial compositions |
US4192766A (en) * | 1975-04-25 | 1980-03-11 | United Chemical Corporation | Composition for decreasing water resistance to movement |
DE2703119A1 (en) * | 1976-01-30 | 1977-08-04 | Fisons Ltd | SODIUMCROMOGLYCAT WITH LESS THAN 5% WATER AND THIS COMPREHENSIVE PHARMACEUTICAL PREPARATIONS |
US4147766A (en) * | 1976-06-09 | 1979-04-03 | Armour Pharmaceutical Company | Macrospherical particles of anti-perspirants |
DE2831419A1 (en) * | 1977-07-19 | 1979-02-01 | Fisons Ltd | Aerosol compsn., pref. contg. fine medicament |
FR2397833A1 (en) * | 1977-07-19 | 1979-02-16 | Fisons Ltd | COMPOSITIONS IN PRESSURE PACKAGING |
US4450151A (en) * | 1978-08-21 | 1984-05-22 | Toyo Aerosol Industry Co., Ltd. | Powder aerosol composition |
US4352789A (en) * | 1980-03-17 | 1982-10-05 | Minnesota Mining And Manufacturing Company | Aerosol compositions containing finely divided solid materials |
EP0047122A3 (en) * | 1980-08-28 | 1983-01-26 | Eli Lilly And Company | Intranasal formulation |
US4605552A (en) * | 1983-07-20 | 1986-08-12 | Warner-Lambert Company | Calcium-antagonist compositions intended for inhalation and process for their manufacture |
JPS60252410A (en) * | 1984-04-25 | 1985-12-13 | イーライ・リリー・アンド・カンパニー | Slow-release nasal medicine and use |
EP0160501A3 (en) * | 1984-04-25 | 1986-12-30 | Eli Lilly And Company | Sustained release intranasal formulation and method of use thereof |
US5681545A (en) * | 1988-12-06 | 1997-10-28 | Riker Laboratories, Inc. | Medicinal aerosol formulations |
US5225183A (en) * | 1988-12-06 | 1993-07-06 | Riker Laboratories, Inc. | Medicinal aerosol formulations |
US5720940A (en) * | 1988-12-06 | 1998-02-24 | Riker Laboratories, Inc. | Medicinal aerosol formulations |
US5605674A (en) * | 1988-12-06 | 1997-02-25 | Riker Laboratories, Inc. | Medicinal aerosol formulations |
US5695743A (en) * | 1988-12-06 | 1997-12-09 | Riker Laboratories, Inc. | Medicinal aerosol formulations |
US5683677A (en) * | 1988-12-06 | 1997-11-04 | Riker Laboratories, Inc. | Medicinal aerosol formulations |
US5674473A (en) * | 1988-12-06 | 1997-10-07 | Riker Laboratories, Inc. | Medicinal aerosol formulations |
US5766573A (en) * | 1988-12-06 | 1998-06-16 | Riker Laboratories, Inc. | Medicinal aerosol formulations |
US6352684B1 (en) | 1988-12-06 | 2002-03-05 | Riker Laboratories Inc. | CRC-free medicinal aerosol formulations of 1,1,1,2-tetrafluoroethane (134A) with polar adjuvant |
US5348730A (en) * | 1989-09-20 | 1994-09-20 | Minnesota Mining And Manufacturing Company | Method for preparing medicinal aerosol formulation containing coated medicament |
US5439670A (en) * | 1989-11-28 | 1995-08-08 | Riker Laboratories, Inc. | Medicinal aerosol formulations |
US20090104127A1 (en) * | 1990-02-03 | 2009-04-23 | Boehringer Ingelheim Kg | Suspension aerosol formulations of pharmaceutical products |
US20050031548A1 (en) * | 1990-02-03 | 2005-02-10 | Boehringer Ingelheim Kg | Suspension aerosol formulations of pharmaceutical products |
US7160538B2 (en) | 1990-02-03 | 2007-01-09 | Boehringer Ingelheim Kg | Suspension aerosol formulations of pharmaceutical products |
US20110014134A1 (en) * | 1990-02-03 | 2011-01-20 | Boehringer Ingelheim Kg | Suspension aerosol formulations of pharmaceutical products |
US6346232B1 (en) | 1990-10-18 | 2002-02-12 | 3M Innovative Properties Company | Method of forming conductive lines |
US5776432A (en) * | 1990-10-18 | 1998-07-07 | Minnesota Mining And Manufacturing Company | Beclomethasone solution aerosol formulations |
US20030198600A1 (en) * | 1991-12-12 | 2003-10-23 | Glaxo Group Limited | Aerosol formulation containing particulate formoterol, propellant and polar cosolvent |
US20030143163A1 (en) * | 1991-12-12 | 2003-07-31 | Glaxo Group Limited | Medicaments |
US20090188491A1 (en) * | 1991-12-12 | 2009-07-30 | Glaxo Group Limited | Medicaments |
US5744123A (en) * | 1991-12-12 | 1998-04-28 | Glaxo Group Limited | Aerosol formulations containing P134a and particulate medicaments |
US5736124A (en) * | 1991-12-12 | 1998-04-07 | Glaxo Group Limited | Aerosol formulations containing P134a and particulate medicament |
US5817293A (en) * | 1991-12-12 | 1998-10-06 | Glaxo Group Limited | Canister containing aerosol formulations containing P134a and particulate medicaments |
US5653962A (en) * | 1991-12-12 | 1997-08-05 | Glaxo Group Limited | Aerosol formulations containing P134a and particulate medicaments |
US7498020B2 (en) | 1991-12-12 | 2009-03-03 | Glaxo Group Limited | Medicaments |
US5922306A (en) * | 1991-12-12 | 1999-07-13 | Glaxo Group Limited | Aerosol formulations containing P134a and particulate medicament |
US5658549A (en) * | 1991-12-12 | 1997-08-19 | Glaxo Group Limited | Aerosol formulations containing propellant 134a and fluticasone propionate |
US20050232873A1 (en) * | 1991-12-12 | 2005-10-20 | Glaxo Group Limited | Aerosol formulation containing particulate formoterol, propellant and polar cosolvent |
US20050207991A1 (en) * | 1991-12-12 | 2005-09-22 | Glaxo Group Limited | Aerosol formulations containing P134a and particulate medicament |
US6919069B2 (en) | 1991-12-12 | 2005-07-19 | Glaxo Group Limited | Aerosol formulation containing particulate formoterol, propellant and polar cosolvent |
US6200549B1 (en) | 1991-12-12 | 2001-03-13 | Glaxo Group Limited | Aerosol formulation containing P134a and particulate medicament |
US6221339B1 (en) | 1991-12-12 | 2001-04-24 | Glaxo Group Limited | Medicaments |
US6238647B1 (en) | 1991-12-12 | 2001-05-29 | Glaxo Group Limited | Aerosol formulations containing salmeterol xinafoate, an anticholinergic agent and tetrafluoroethane |
US6251368B1 (en) | 1991-12-12 | 2001-06-26 | Glaxo Group Limited | Pharmaceutical aerosol formulation containing a particulate medicament, a propellant and substantially free of a surfactant |
US6893628B2 (en) | 1991-12-12 | 2005-05-17 | Glaxo Group Limited | Aerosol formulations containing P134a and particulate medicament |
US6303103B1 (en) | 1991-12-12 | 2001-10-16 | Glaxo Group Limited | Aerosols containing salmeterol xinafoate and an anticholinergic medicament |
US20050089477A1 (en) * | 1991-12-12 | 2005-04-28 | Glaxo Group Limited | Medicaments |
US6306369B1 (en) | 1991-12-12 | 2001-10-23 | Glaxo Group Limited | Aerosol formulations containing P134a and particulate medicament |
US5674471A (en) * | 1991-12-12 | 1997-10-07 | Glaxo Group Limited | Aerosol formulations containing P134a and salbutamol |
US6333023B1 (en) | 1991-12-12 | 2001-12-25 | Glaxo Group Limited | Aerosol formulation containing particulate formoterol, propellant and polar cosolvent |
US5674472A (en) * | 1991-12-12 | 1997-10-07 | Glaxo Group Limited | Canisters containing aerosol formulations containing P134a and fluticasone propionate |
US5683676A (en) * | 1991-12-12 | 1997-11-04 | Glaxo Group Limited | Canister containing aerosol formulations containing P134a and particulate medicaments |
US5676929A (en) * | 1991-12-12 | 1997-10-14 | Glaxo Group Limited | Canister containing aerosol formulations containing P134a and particulate medicaments |
US20030165437A1 (en) * | 1991-12-12 | 2003-09-04 | Glaxo Group Limited | Aerosos formulations containing P134a and particulate medicament |
US7101534B1 (en) | 1991-12-18 | 2006-09-05 | 3M Innovative Properties Company | Suspension aerosol formulations |
US6743413B1 (en) | 1991-12-18 | 2004-06-01 | 3M Company | Suspension aerosol formulations |
US7105152B1 (en) | 1991-12-18 | 2006-09-12 | 3M Innovative Properties Company | Suspension aerosol formulations |
US20040197273A1 (en) * | 1991-12-18 | 2004-10-07 | 3M Company | Suspension aerosol formulations |
US5756071A (en) * | 1992-06-03 | 1998-05-26 | Arrowdean Limited | Method for nasally administering aerosols of therapeutic agents to enhance penetration of the blood brain barrier |
US5368842A (en) * | 1992-10-29 | 1994-11-29 | The Gillette Company | High efficacy aerosol antiperspirant composition |
US6846801B1 (en) | 1993-06-24 | 2005-01-25 | Astrazeneca Ab | Systemic administration of a therapeutic preparation |
US20040171550A1 (en) * | 1993-06-24 | 2004-09-02 | Astrazeneca Ab, A Swedish Corporation | Compositions for inhalation |
US5747445A (en) * | 1993-06-24 | 1998-05-05 | Astra Aktiebolag | Therapeutic preparation for inhalation |
US6632456B1 (en) | 1993-06-24 | 2003-10-14 | Astrazeneca Ab | Compositions for inhalation |
US5952008A (en) * | 1993-06-24 | 1999-09-14 | Ab Astra | Processes for preparing compositions for inhalation |
US6306440B1 (en) | 1993-06-24 | 2001-10-23 | Astrazeneca Ab | Therapeutic preparation for inhalation |
US20030211972A1 (en) * | 1993-06-24 | 2003-11-13 | Astrazeneca Ab, A Sweden Corporation | Systemic administration of a therapeutic preparation |
US20030216541A1 (en) * | 1993-06-24 | 2003-11-20 | Astrazeneca Ab, A Swedish Corporation | Systemic administration of a therapeutic preparation |
US6794357B1 (en) | 1993-06-24 | 2004-09-21 | Astrazeneca Ab | Compositions for inhalation |
US5830853A (en) * | 1994-06-23 | 1998-11-03 | Astra Aktiebolag | Systemic administration of a therapeutic preparation |
US6610653B1 (en) | 1994-06-23 | 2003-08-26 | Astrazeneca Ab | Therapeutic preparation for inhalation |
US5916540A (en) * | 1994-10-24 | 1999-06-29 | Glaxo Group Limited | Aerosol formulations containing P134A and/or P227 and particulate medicament |
US6524557B1 (en) | 1994-12-22 | 2003-02-25 | Astrazeneca Ab | Aerosol formulations of peptides and proteins |
US6004574A (en) * | 1994-12-22 | 1999-12-21 | Astra Aktiebolag | Powder formulations containing melezitose as a diluent |
US20030064928A1 (en) * | 1994-12-22 | 2003-04-03 | Astra Aktiebolag, A Sweden Corporation | Therapeutic preparations for inhalation |
US6436902B1 (en) | 1994-12-22 | 2002-08-20 | Astrazeneca Ab | Therapeutic preparations for inhalation |
US6932962B1 (en) | 1994-12-22 | 2005-08-23 | Astrazeneca Ab | Aerosol drug formulations containing hydrofluoroalkanes and alkyl saccharides |
US6054488A (en) * | 1996-06-11 | 2000-04-25 | 3M Innovative Properties Company | Medicinal aerosol formulations of formoterol |
US7566445B1 (en) | 1996-08-01 | 2009-07-28 | Norton Healthcare Limited | Medicinal aerosols and methods of delivery thereof |
US20090246148A1 (en) * | 1996-08-01 | 2009-10-01 | Norton Healthcare Ltd | Medicinal aerosols and methods of delivery thereof |
US8834849B2 (en) | 1996-08-01 | 2014-09-16 | Norton Healthcare Limited | Medicinal aerosols and methods of delivery thereof |
US9650203B2 (en) | 1996-08-01 | 2017-05-16 | Norton Healthcare Limited | Medicinal aerosols and methods of delivery thereof |
US6461591B1 (en) | 1997-02-05 | 2002-10-08 | Jago Research Ag | Medical aerosol formulations |
US7628978B2 (en) | 1997-09-29 | 2009-12-08 | Novartis Pharma Ag | Stabilized preparations for use in metered dose inhalers |
US6565885B1 (en) | 1997-09-29 | 2003-05-20 | Inhale Therapeutic Systems, Inc. | Methods of spray drying pharmaceutical compositions |
US8080263B2 (en) | 1997-09-29 | 2011-12-20 | Novartis Ag | Dispersion for pulmonary delivery of a bioactive agent |
US6946117B1 (en) | 1997-09-29 | 2005-09-20 | Nektar Therapeutics | Stabilized preparations for use in nebulizers |
US8168223B1 (en) | 1997-09-29 | 2012-05-01 | Novartis Pharma Ag | Engineered particles and methods of use |
US7205343B2 (en) | 1997-09-29 | 2007-04-17 | Dellamary Luis A | Stabilized bioactive preparations and method of use |
US7306787B2 (en) | 1997-09-29 | 2007-12-11 | Nektar Therapeutics | Engineered particles and methods of use |
US20050207986A1 (en) * | 1997-09-29 | 2005-09-22 | Schutt Ernest G | Stabilized preparations for use in nebulizers |
US7393544B2 (en) | 1997-09-29 | 2008-07-01 | Nektar Therapeutics | Dispersion for pulmonary delivery of a bioactive agent |
US9554993B2 (en) | 1997-09-29 | 2017-01-31 | Novartis Ag | Pulmonary delivery particles comprising an active agent |
US6433040B1 (en) | 1997-09-29 | 2002-08-13 | Inhale Therapeutic Systems, Inc. | Stabilized bioactive preparations and methods of use |
US8246934B2 (en) | 1997-09-29 | 2012-08-21 | Novartis Ag | Respiratory dispersion for metered dose inhalers comprising perforated microstructures |
US6638495B2 (en) | 1997-09-29 | 2003-10-28 | Nektar Therapeutics | Stabilized preparation for use in metered dose inhalers |
US6309623B1 (en) | 1997-09-29 | 2001-10-30 | Inhale Therapeutic Systems, Inc. | Stabilized preparations for use in metered dose inhalers |
US20020010318A1 (en) * | 1997-10-03 | 2002-01-24 | Amgen, Inc. | Secretory leukocyte protease inhibitor dry powder pharmaceutical compositions |
WO1999065460A3 (en) * | 1998-06-19 | 2000-04-27 | Baker Norton Pharma | Pressurized metered dose inhalers and pharmaceutical aerosol formulations comprising a beta-agonist |
US6451285B2 (en) | 1998-06-19 | 2002-09-17 | Baker Norton Pharmaceuticals, Inc. | Suspension aerosol formulations containing formoterol fumarate and a fluoroalkane propellant |
EP1306082A1 (en) * | 1998-06-19 | 2003-05-02 | Baker Norton Pharmaceuticals, Inc. | Pressurized metered dose inhalers and pharmaceutical aerosol formulations |
US6585958B1 (en) | 1998-07-24 | 2003-07-01 | Jago Research Ag | Medicinal aerosol formulations |
US6475467B1 (en) | 1998-08-04 | 2002-11-05 | Jago Research Ag | Medicinal aerosol formulations |
US6290930B1 (en) | 1998-12-18 | 2001-09-18 | Baker Norton Pharmaceuticals, Inc. | Pharmaceutical solution aerosol formulations containing fluoroalkanes and budesonide |
US7442388B2 (en) | 2000-05-10 | 2008-10-28 | Weers Jeffry G | Phospholipid-based powders for drug delivery |
US8349294B2 (en) | 2000-05-10 | 2013-01-08 | Novartis Ag | Stable metal ion-lipid powdered pharmaceutical compositions for drug delivery and methods of use |
US9439862B2 (en) | 2000-05-10 | 2016-09-13 | Novartis Ag | Phospholipid-based powders for drug delivery |
US8877162B2 (en) | 2000-05-10 | 2014-11-04 | Novartis Ag | Stable metal ion-lipid powdered pharmaceutical compositions for drug delivery |
US8709484B2 (en) | 2000-05-10 | 2014-04-29 | Novartis Ag | Phospholipid-based powders for drug delivery |
US7871598B1 (en) | 2000-05-10 | 2011-01-18 | Novartis Ag | Stable metal ion-lipid powdered pharmaceutical compositions for drug delivery and methods of use |
US8404217B2 (en) | 2000-05-10 | 2013-03-26 | Novartis Ag | Formulation for pulmonary administration of antifungal agents, and associated methods of manufacture and use |
US7368102B2 (en) | 2001-12-19 | 2008-05-06 | Nektar Therapeutics | Pulmonary delivery of aminoglycosides |
US9421166B2 (en) | 2001-12-19 | 2016-08-23 | Novartis Ag | Pulmonary delivery of aminoglycoside |
US8715623B2 (en) | 2001-12-19 | 2014-05-06 | Novartis Ag | Pulmonary delivery of aminoglycoside |
US8470301B2 (en) | 2002-04-17 | 2013-06-25 | Nektar Therapeutics | Particulate materials |
US8828359B2 (en) | 2002-04-17 | 2014-09-09 | Nektar Therapeutics | Particulate materials |
US9616060B2 (en) | 2002-04-17 | 2017-04-11 | Nektar Therapeutics | Particulate materials |
US8080236B2 (en) | 2002-04-17 | 2011-12-20 | Nektar Therapeutics Uk, Ltd | Particulate materials |
US7582284B2 (en) | 2002-04-17 | 2009-09-01 | Nektar Therapeutics | Particulate materials |
US10251881B2 (en) | 2002-04-17 | 2019-04-09 | Nektar Therapeutics | Particulate materials |
US9808423B2 (en) | 2004-10-12 | 2017-11-07 | Generics [Uk] Limited | Preparation of suspension aerosol formulations |
EP1949891A1 (en) | 2004-10-12 | 2008-07-30 | Generics (UK) Limited | Process for the preparation of suspension aerosol formulations, wherein the particles are formed by precipitation inside an aerosol canister |
US20090297457A1 (en) * | 2004-10-12 | 2009-12-03 | Generics [Uk] Limited | Preparation Of Suspension Aerosol Formulations |
US8524734B2 (en) | 2005-05-18 | 2013-09-03 | Mpex Pharmaceuticals, Inc. | Aerosolized fluoroquinolones and uses thereof |
US8524735B2 (en) | 2005-05-18 | 2013-09-03 | Mpex Pharmaceuticals, Inc. | Aerosolized fluoroquinolones and uses thereof |
US8546423B2 (en) | 2005-05-18 | 2013-10-01 | Mpex Pharmaceuticals, Inc. | Aerosolized fluoroquinolones and uses thereof |
US10987357B2 (en) | 2005-05-18 | 2021-04-27 | Horizon Orphan, LLC | Aerosolized fluoroquinolones and uses thereof |
EP2594272A2 (en) | 2005-05-18 | 2013-05-22 | Mpex Pharmaceuticals, Inc. | Aerosolized fluoroquinolones and uses thereof |
US8357696B2 (en) | 2005-05-18 | 2013-01-22 | Mpex Pharmaceuticals, Inc. | Aerosolized fluoroquinolones and uses thereof |
US8367734B1 (en) | 2005-08-11 | 2013-02-05 | Amphastar Pharmaceuticals Inc. | Stable epinephrine suspension formulation with high inhalation delivery efficiency |
US20090191134A1 (en) * | 2006-06-12 | 2009-07-30 | Medispray Laboratoriespvt. Ltd. | Stable aerosol pharmaceutical formulations |
US7994197B2 (en) | 2007-02-11 | 2011-08-09 | Map Pharmaceuticals, Inc. | Method of therapeutic administration of DHE to enable rapid relief of migraine while minimizing side effect profile |
US8148377B2 (en) | 2007-02-11 | 2012-04-03 | Map Pharmaceuticals, Inc. | Method of therapeutic administration of DHE to enable rapid relief of migraine while minimizing side effect profile |
US8119639B2 (en) | 2007-02-11 | 2012-02-21 | Map Pharmaceuticals, Inc. | Method of therapeutic administration of DHE to enable rapid relief of migraine while minimizing side effect profile |
US20080287451A1 (en) * | 2007-02-11 | 2008-11-20 | Cook Robert O | Method of therapeutic administration of DHE to enable rapid relief of migraine while minimizing side effect profile |
US10172853B2 (en) | 2007-02-11 | 2019-01-08 | Map Pharmaceuticals, Inc. | Method of therapeutic administration of DHE to enable rapid relief of migraine while minimizing side effect profile |
US9833451B2 (en) | 2007-02-11 | 2017-12-05 | Map Pharmaceuticals, Inc. | Method of therapeutic administration of DHE to enable rapid relief of migraine while minimizing side effect profile |
US8629139B2 (en) | 2008-10-07 | 2014-01-14 | Mpex Pharmaceuticals, Inc. | Topical use of Levofloxacin for reducing lung inflammation |
US9717738B2 (en) | 2008-10-07 | 2017-08-01 | Horizon Orphan Llc | Aerosol fluoroquinolone formulations for improved pharmacokinetics |
US11020481B2 (en) | 2008-10-07 | 2021-06-01 | Horizon Orphan Llc | Topical use of levofloxacin for reducing lung inflammation |
US10149854B2 (en) | 2008-10-07 | 2018-12-11 | Horizon Orphan Llc | Aerosol fluoroquinolone formulations for improved pharmacokinetics |
US8815838B2 (en) | 2008-10-07 | 2014-08-26 | David C. Griffith | Aerosol fluoroquinolone formulations for improved pharmacokinetics |
US9326936B2 (en) | 2008-10-07 | 2016-05-03 | Raptor Pharmaceuticals, Inc. | Aerosol fluoroquinolone formulations for improved pharmacokinetics |
US10722519B2 (en) | 2008-10-07 | 2020-07-28 | Horizon Orphan Llc | Aerosol fluoroquinolone formulations for improved pharmacokinetics |
US9700564B2 (en) | 2009-09-04 | 2017-07-11 | Horizon Orphan Llc | Use of aerosolized levofloxacin for treating cystic fibrosis |
US10231975B2 (en) | 2009-09-04 | 2019-03-19 | Horizon Orphan Llc | Use of aerosolized levofloxacin for treating cystic fibrosis |
US10792289B2 (en) | 2009-09-04 | 2020-10-06 | Horizon Orphan Llc | Use of aerosolized levofloxacin for treating cystic fibrosis |
WO2012106382A1 (en) | 2011-01-31 | 2012-08-09 | Genoa Pharmaceuticals, Inc. | Aerosol pirfenidone and pyridone analog compounds and uses thereof |
EP4059499A1 (en) | 2011-01-31 | 2022-09-21 | Avalyn Pharma Inc. | Aerosol pirfenidone and pyridone analog compounds and uses thereof |
EP3782604A1 (en) | 2013-07-31 | 2021-02-24 | Windward Pharma, Inc. | Aerosol tyrosine kinase inhibitor compounds and uses thereof |
US10028966B2 (en) | 2014-01-10 | 2018-07-24 | Avalyn Pharma Inc. | Aerosol pirfenidone and pyridone analog compounds and uses thereof |
EP4491180A1 (en) | 2014-01-10 | 2025-01-15 | Avalyn Pharma Inc. | Aerosol pirfenidone and pyridone analog compounds and uses thereof |
US11633556B2 (en) | 2017-09-22 | 2023-04-25 | Imperial Tobacco Limited | Aerosolization using two aerosol generators |
US12029846B2 (en) | 2017-09-22 | 2024-07-09 | Imperial Tobacco Limited | Aerosolization using two aerosol generators |
US12059525B2 (en) | 2017-09-22 | 2024-08-13 | Nerudia Limited | Substitute smoking device comprising multiple aerosols and passive aerosol generation |
US12337105B2 (en) | 2017-09-22 | 2025-06-24 | Imperial Tobacco Limited | Aerosolization using two aerosol generators |
WO2022240897A1 (en) | 2021-05-10 | 2022-11-17 | Sepelo Therapeutics, Llc | Pharmaceutical composition comprising delafloxacin for administration into the lung |
WO2023028364A1 (en) | 2021-08-27 | 2023-03-02 | Sepelo Therapeutics, Llc | Targeted compositions and uses therof |
Also Published As
Publication number | Publication date |
---|---|
DE1178975B (en) | 1964-10-01 |
NL106832C (en) | 1963-12-16 |
NL224547A (en) | |
BE556587A (en) | 1957-04-11 |
GB837465A (en) | 1960-06-15 |
FR1228811A (en) | 1960-09-02 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US3014844A (en) | Self-propelling powder dispensing compositions | |
US5334374A (en) | Pharmaceutical compositions containing pentamidine | |
US5204113A (en) | Pharmaceutical compositions containing pentamidine | |
JP4570251B2 (en) | Pharmaceutical aerosol formulation | |
AU718967B2 (en) | Medical aerosol formulations | |
RU2294737C2 (en) | Medicinal aerosol compositions | |
CA2352483C (en) | Pharmaceutical aerosol composition containing hfa 227 and hfa 134a | |
US5292499A (en) | Method of preparing medical aerosol formulations including drug dissolved in reverse micelles | |
RU2129424C1 (en) | Aerosol pharmaceutical composition, a method of treatment of patients with respiratory diseases | |
AU749697B2 (en) | Medicinal aerosol formulations | |
EP0499344B1 (en) | Medicinal aerosol formulations | |
US3169095A (en) | Self-propelling powder-dispensing compositions | |
US20070253913A1 (en) | Aerosol formulations for delivery of dihydroergotamine to the systemic circulation via pulmonary inhalation | |
AU2002211311B2 (en) | Medicinal aerosol formulations | |
SK140593A3 (en) | Non-chlorofluorocarbon aerosol formulations | |
JPH10510521A (en) | Propellant mixture for aerosol formulations | |
HUP0001339A2 (en) | Pharmaceutical aerosol composition | |
WO1990011754A1 (en) | Aerosolized azole antifungals | |
US6129905A (en) | Aerosol formulations containing a sugar as a dispersant | |
CA1083963A (en) | Use of flunisolide to treat respiratory diseases | |
AU774250B2 (en) | Pharmaceutical aerosol composition | |
SE178687C1 (en) | ||
ITMI982559A1 (en) | "DOSED INHALERS FOR PRESSURIZERS" |