US20040213744A1 - Topical spray compositions - Google Patents
Topical spray compositions Download PDFInfo
- Publication number
- US20040213744A1 US20040213744A1 US10/686,517 US68651703A US2004213744A1 US 20040213744 A1 US20040213744 A1 US 20040213744A1 US 68651703 A US68651703 A US 68651703A US 2004213744 A1 US2004213744 A1 US 2004213744A1
- Authority
- US
- United States
- Prior art keywords
- composition
- composition according
- medicament
- film
- canceled
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 154
- 229940041677 topical spray Drugs 0.000 title description 5
- 239000003814 drug Substances 0.000 claims abstract description 86
- 229940079593 drug Drugs 0.000 claims abstract description 35
- 239000002904 solvent Substances 0.000 claims abstract description 26
- 230000000699 topical effect Effects 0.000 claims abstract description 24
- 239000004014 plasticizer Substances 0.000 claims abstract description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000003961 penetration enhancing agent Substances 0.000 claims abstract description 14
- 239000000654 additive Substances 0.000 claims abstract description 13
- 230000000996 additive effect Effects 0.000 claims abstract description 8
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 63
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 33
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims description 28
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 28
- 239000003380 propellant Substances 0.000 claims description 27
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 23
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 23
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 21
- 229920001577 copolymer Polymers 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 16
- 239000003981 vehicle Substances 0.000 claims description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- 229930003427 Vitamin E Natural products 0.000 claims description 14
- -1 anti-anginals Substances 0.000 claims description 14
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 claims description 14
- 229940046009 vitamin E Drugs 0.000 claims description 14
- 235000019165 vitamin E Nutrition 0.000 claims description 14
- 239000011709 vitamin E Substances 0.000 claims description 14
- 239000004479 aerosol dispenser Substances 0.000 claims description 13
- 239000002202 Polyethylene glycol Substances 0.000 claims description 10
- 229920001223 polyethylene glycol Polymers 0.000 claims description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- 150000005846 sugar alcohols Polymers 0.000 claims description 9
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 claims description 8
- SOGAXMICEFXMKE-UHFFFAOYSA-N Butylmethacrylate Chemical compound CCCCOC(=O)C(C)=C SOGAXMICEFXMKE-UHFFFAOYSA-N 0.000 claims description 8
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 8
- 229960005309 estradiol Drugs 0.000 claims description 8
- 229930182833 estradiol Natural products 0.000 claims description 8
- 229940069328 povidone Drugs 0.000 claims description 8
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 8
- XXJWXESWEXIICW-UHFFFAOYSA-N diethylene glycol monoethyl ether Chemical compound CCOCCOCCO XXJWXESWEXIICW-UHFFFAOYSA-N 0.000 claims description 7
- 239000003906 humectant Substances 0.000 claims description 7
- 239000004094 surface-active agent Substances 0.000 claims description 7
- 230000009885 systemic effect Effects 0.000 claims description 7
- MEJYDZQQVZJMPP-ULAWRXDQSA-N (3s,3ar,6r,6ar)-3,6-dimethoxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan Chemical compound CO[C@H]1CO[C@@H]2[C@H](OC)CO[C@@H]21 MEJYDZQQVZJMPP-ULAWRXDQSA-N 0.000 claims description 6
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- DJLHXXNSHHGFLB-UHFFFAOYSA-N ethyl 2-methylprop-2-enoate;n-methylmethanamine Chemical compound CNC.CCOC(=O)C(C)=C DJLHXXNSHHGFLB-UHFFFAOYSA-N 0.000 claims description 6
- 125000005397 methacrylic acid ester group Chemical group 0.000 claims description 6
- 230000007935 neutral effect Effects 0.000 claims description 6
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 claims description 6
- 229940029284 trichlorofluoromethane Drugs 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 238000005507 spraying Methods 0.000 claims description 5
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims description 4
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 claims description 4
- GHVNFZFCNZKVNT-UHFFFAOYSA-N Decanoic acid Natural products CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 claims description 4
- 239000004338 Dichlorodifluoromethane Substances 0.000 claims description 4
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- RKUNBYITZUJHSG-UHFFFAOYSA-N Hyosciamin-hydrochlorid Natural products CN1C(C2)CCC1CC2OC(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-UHFFFAOYSA-N 0.000 claims description 4
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 claims description 4
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 claims description 4
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 claims description 4
- YASAKCUCGLMORW-UHFFFAOYSA-N Rosiglitazone Chemical compound C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O YASAKCUCGLMORW-UHFFFAOYSA-N 0.000 claims description 4
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 claims description 4
- AOBORMOPSGHCAX-UHFFFAOYSA-N Tocophersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-UHFFFAOYSA-N 0.000 claims description 4
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 4
- 235000019404 dichlorodifluoromethane Nutrition 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 230000003054 hormonal effect Effects 0.000 claims description 4
- 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 claims description 4
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 claims 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 claims description 4
- NNPPMTNAJDCUHE-UHFFFAOYSA-N isobutane Chemical compound CC(C)C NNPPMTNAJDCUHE-UHFFFAOYSA-N 0.000 claims description 4
- 229940041616 menthol Drugs 0.000 claims description 4
- 229940117841 methacrylic acid copolymer Drugs 0.000 claims description 4
- 229920003145 methacrylic acid copolymer Polymers 0.000 claims description 4
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 claims description 4
- 150000003431 steroids Chemical class 0.000 claims description 4
- LVGUZGTVOIAKKC-UHFFFAOYSA-N 1,1,1,2-tetrafluoroethane Chemical compound FCC(F)(F)F LVGUZGTVOIAKKC-UHFFFAOYSA-N 0.000 claims description 3
- 239000005541 ACE inhibitor Substances 0.000 claims description 3
- OGSPWJRAVKPPFI-UHFFFAOYSA-N Alendronic Acid Chemical compound NCCCC(O)(P(O)(O)=O)P(O)(O)=O OGSPWJRAVKPPFI-UHFFFAOYSA-N 0.000 claims description 3
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 claims description 3
- 229940127291 Calcium channel antagonist Drugs 0.000 claims description 3
- 208000010228 Erectile Dysfunction Diseases 0.000 claims description 3
- 206010021639 Incontinence Diseases 0.000 claims description 3
- 208000021384 Obsessive-Compulsive disease Diseases 0.000 claims description 3
- 208000001132 Osteoporosis Diseases 0.000 claims description 3
- 208000004403 Prostatic Hyperplasia Diseases 0.000 claims description 3
- 206010046555 Urinary retention Diseases 0.000 claims description 3
- 229920006243 acrylic copolymer Polymers 0.000 claims description 3
- 229960004343 alendronic acid Drugs 0.000 claims description 3
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 claims description 3
- 230000003257 anti-anginal effect Effects 0.000 claims description 3
- 230000001142 anti-diarrhea Effects 0.000 claims description 3
- 230000003474 anti-emetic effect Effects 0.000 claims description 3
- 239000000883 anti-obesity agent Substances 0.000 claims description 3
- 229940125681 anticonvulsant agent Drugs 0.000 claims description 3
- 239000001961 anticonvulsive agent Substances 0.000 claims description 3
- 239000000935 antidepressant agent Substances 0.000 claims description 3
- 229940005513 antidepressants Drugs 0.000 claims description 3
- 239000003472 antidiabetic agent Substances 0.000 claims description 3
- 229940125708 antidiabetic agent Drugs 0.000 claims description 3
- 239000002111 antiemetic agent Substances 0.000 claims description 3
- 229940030600 antihypertensive agent Drugs 0.000 claims description 3
- 239000002220 antihypertensive agent Substances 0.000 claims description 3
- 229940082992 antihypertensives mao inhibitors Drugs 0.000 claims description 3
- 229940125684 antimigraine agent Drugs 0.000 claims description 3
- 239000002282 antimigraine agent Substances 0.000 claims description 3
- 239000000939 antiparkinson agent Substances 0.000 claims description 3
- 229940125688 antiparkinson agent Drugs 0.000 claims description 3
- 239000002249 anxiolytic agent Substances 0.000 claims description 3
- 230000000949 anxiolytic effect Effects 0.000 claims description 3
- 229940005530 anxiolytics Drugs 0.000 claims description 3
- 239000003125 aqueous solvent Substances 0.000 claims description 3
- 229940124630 bronchodilator Drugs 0.000 claims description 3
- 239000000480 calcium channel blocker Substances 0.000 claims description 3
- 239000004359 castor oil Substances 0.000 claims description 3
- 235000019438 castor oil Nutrition 0.000 claims description 3
- 239000002934 diuretic Substances 0.000 claims description 3
- 229940030606 diuretics Drugs 0.000 claims description 3
- 229940052760 dopamine agonists Drugs 0.000 claims description 3
- 239000003136 dopamine receptor stimulating agent Substances 0.000 claims description 3
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 3
- 201000001881 impotence Diseases 0.000 claims description 3
- 239000002899 monoamine oxidase inhibitor Substances 0.000 claims description 3
- 229920000058 polyacrylate Polymers 0.000 claims description 3
- 229920000136 polysorbate Polymers 0.000 claims description 3
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 3
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 3
- 208000019116 sleep disease Diseases 0.000 claims description 3
- AHOUBRCZNHFOSL-YOEHRIQHSA-N (+)-Casbol Chemical compound C1=CC(F)=CC=C1[C@H]1[C@H](COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-YOEHRIQHSA-N 0.000 claims description 2
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 claims description 2
- DIWRORZWFLOCLC-HNNXBMFYSA-N (3s)-7-chloro-5-(2-chlorophenyl)-3-hydroxy-1,3-dihydro-1,4-benzodiazepin-2-one Chemical compound N([C@H](C(NC1=CC=C(Cl)C=C11)=O)O)=C1C1=CC=CC=C1Cl DIWRORZWFLOCLC-HNNXBMFYSA-N 0.000 claims description 2
- GMVPRGQOIOIIMI-UHFFFAOYSA-N (8R,11R,12R,13E,15S)-11,15-Dihydroxy-9-oxo-13-prostenoic acid Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CCCCCCC(O)=O GMVPRGQOIOIIMI-UHFFFAOYSA-N 0.000 claims description 2
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 claims description 2
- RTHCYVBBDHJXIQ-MRXNPFEDSA-N (R)-fluoxetine Chemical compound O([C@H](CCNC)C=1C=CC=CC=1)C1=CC=C(C(F)(F)F)C=C1 RTHCYVBBDHJXIQ-MRXNPFEDSA-N 0.000 claims description 2
- RKUNBYITZUJHSG-FXUDXRNXSA-N (S)-atropine Chemical compound C1([C@@H](CO)C(=O)O[C@H]2C[C@H]3CC[C@@H](C2)N3C)=CC=CC=C1 RKUNBYITZUJHSG-FXUDXRNXSA-N 0.000 claims description 2
- WLRMANUAADYWEA-NWASOUNVSA-N (S)-timolol maleate Chemical compound OC(=O)\C=C/C(O)=O.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1 WLRMANUAADYWEA-NWASOUNVSA-N 0.000 claims description 2
- FRCHKSNAZZFGCA-UHFFFAOYSA-N 1,1-dichloro-1-fluoroethane Chemical compound CC(F)(Cl)Cl FRCHKSNAZZFGCA-UHFFFAOYSA-N 0.000 claims description 2
- NPNPZTNLOVBDOC-UHFFFAOYSA-N 1,1-difluoroethane Chemical compound CC(F)F NPNPZTNLOVBDOC-UHFFFAOYSA-N 0.000 claims description 2
- DDMOUSALMHHKOS-UHFFFAOYSA-N 1,2-dichloro-1,1,2,2-tetrafluoroethane Chemical compound FC(F)(Cl)C(F)(F)Cl DDMOUSALMHHKOS-UHFFFAOYSA-N 0.000 claims description 2
- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 claims description 2
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 claims 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 claims description 2
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 claims description 2
- RZTAMFZIAATZDJ-HNNXBMFYSA-N 5-o-ethyl 3-o-methyl (4s)-4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC(Cl)=C1Cl RZTAMFZIAATZDJ-HNNXBMFYSA-N 0.000 claims description 2
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 claims description 2
- 229930000680 A04AD01 - Scopolamine Natural products 0.000 claims description 2
- QZCLKYGREBVARF-UHFFFAOYSA-N Acetyl tributyl citrate Chemical compound CCCCOC(=O)CC(C(=O)OCCCC)(OC(C)=O)CC(=O)OCCCC QZCLKYGREBVARF-UHFFFAOYSA-N 0.000 claims description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 2
- 229930003347 Atropine Natural products 0.000 claims description 2
- KUVIULQEHSCUHY-XYWKZLDCSA-N Beclometasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)COC(=O)CC)(OC(=O)CC)[C@@]1(C)C[C@@H]2O KUVIULQEHSCUHY-XYWKZLDCSA-N 0.000 claims description 2
- VOVIALXJUBGFJZ-KWVAZRHASA-N Budesonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(CCC)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O VOVIALXJUBGFJZ-KWVAZRHASA-N 0.000 claims description 2
- KORNTPPJEAJQIU-KJXAQDMKSA-N Cabaser Chemical compound C1=CC([C@H]2C[C@H](CN(CC=C)[C@@H]2C2)C(=O)N(CCCN(C)C)C(=O)NCC)=C3C2=CNC3=C1 KORNTPPJEAJQIU-KJXAQDMKSA-N 0.000 claims description 2
- 239000005632 Capric acid (CAS 334-48-5) Substances 0.000 claims description 2
- 239000005635 Caprylic acid (CAS 124-07-2) Substances 0.000 claims description 2
- VOPWNXZWBYDODV-UHFFFAOYSA-N Chlorodifluoromethane Chemical compound FC(F)Cl VOPWNXZWBYDODV-UHFFFAOYSA-N 0.000 claims description 2
- GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- HCYAFALTSJYZDH-UHFFFAOYSA-N Desimpramine Chemical compound C1CC2=CC=CC=C2N(CCCNC)C2=CC=CC=C21 HCYAFALTSJYZDH-UHFFFAOYSA-N 0.000 claims description 2
- XIQVNETUBQGFHX-UHFFFAOYSA-N Ditropan Chemical compound C=1C=CC=CC=1C(O)(C(=O)OCC#CCN(CC)CC)C1CCCCC1 XIQVNETUBQGFHX-UHFFFAOYSA-N 0.000 claims description 2
- 239000001856 Ethyl cellulose Substances 0.000 claims description 2
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 2
- DBVJJBKOTRCVKF-UHFFFAOYSA-N Etidronic acid Chemical compound OP(=O)(O)C(O)(C)P(O)(O)=O DBVJJBKOTRCVKF-UHFFFAOYSA-N 0.000 claims description 2
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- 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 claims description 2
- 229960002646 scopolamine Drugs 0.000 claims description 2
- 229960003466 sibutramine hydrochloride Drugs 0.000 claims description 2
- 229960002639 sildenafil citrate Drugs 0.000 claims description 2
- DEIYFTQMQPDXOT-UHFFFAOYSA-N sildenafil citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 DEIYFTQMQPDXOT-UHFFFAOYSA-N 0.000 claims description 2
- 230000005586 smoking cessation Effects 0.000 claims description 2
- JGMJQSFLQWGYMQ-UHFFFAOYSA-M sodium;2,6-dichloro-n-phenylaniline;acetate Chemical compound [Na+].CC([O-])=O.ClC1=CC=CC(Cl)=C1NC1=CC=CC=C1 JGMJQSFLQWGYMQ-UHFFFAOYSA-M 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 239000003270 steroid hormone Substances 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 2
- KQKPFRSPSRPDEB-UHFFFAOYSA-N sumatriptan Chemical compound CNS(=O)(=O)CC1=CC=C2NC=C(CCN(C)C)C2=C1 KQKPFRSPSRPDEB-UHFFFAOYSA-N 0.000 claims description 2
- 229960003708 sumatriptan Drugs 0.000 claims description 2
- 229960002613 tamsulosin Drugs 0.000 claims description 2
- 229960001693 terazosin Drugs 0.000 claims description 2
- VCKUSRYTPJJLNI-UHFFFAOYSA-N terazosin Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1CCCO1 VCKUSRYTPJJLNI-UHFFFAOYSA-N 0.000 claims description 2
- 229960003604 testosterone Drugs 0.000 claims description 2
- 238000002560 therapeutic procedure Methods 0.000 claims description 2
- PBJUNZJWGZTSKL-MRXNPFEDSA-N tiagabine Chemical compound C1=CSC(C(=CCCN2C[C@@H](CCC2)C(O)=O)C2=C(C=CS2)C)=C1C PBJUNZJWGZTSKL-MRXNPFEDSA-N 0.000 claims description 2
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- 229960005221 timolol maleate Drugs 0.000 claims description 2
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- 239000001069 triethyl citrate Substances 0.000 claims description 2
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 claims description 2
- 235000013769 triethyl citrate Nutrition 0.000 claims description 2
- 229960001032 trihexyphenidyl Drugs 0.000 claims description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims description 2
- 229960000281 trometamol Drugs 0.000 claims description 2
- 229960003726 vasopressin Drugs 0.000 claims description 2
- 229960001722 verapamil Drugs 0.000 claims description 2
- 229960001360 zolmitriptan Drugs 0.000 claims description 2
- UTAZCRNOSWWEFR-ZDUSSCGKSA-N zolmitriptan Chemical compound C=1[C]2C(CCN(C)C)=CN=C2C=CC=1C[C@H]1COC(=O)N1 UTAZCRNOSWWEFR-ZDUSSCGKSA-N 0.000 claims description 2
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 claims 3
- XSOCXEILAGSIKB-UHFFFAOYSA-N ethyl acetate;1,1,1-trichloro-2-fluoroethane Chemical compound CCOC(C)=O.FCC(Cl)(Cl)Cl XSOCXEILAGSIKB-UHFFFAOYSA-N 0.000 claims 2
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 claims 1
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 claims 1
- OHMHBGPWCHTMQE-UHFFFAOYSA-N 2,2-dichloro-1,1,1-trifluoroethane Chemical compound FC(F)(F)C(Cl)Cl OHMHBGPWCHTMQE-UHFFFAOYSA-N 0.000 claims 1
- JNKZWBJAPFIKNY-UHFFFAOYSA-N 2,3-dimethyl-4-octylbenzoic acid Chemical compound CCCCCCCCC1=CC=C(C(O)=O)C(C)=C1C JNKZWBJAPFIKNY-UHFFFAOYSA-N 0.000 claims 1
- 239000004215 Carbon black (E152) Substances 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims 1
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- 239000004698 Polyethylene Substances 0.000 claims 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims 1
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- 229940053934 norethindrone Drugs 0.000 claims 1
- VIKNJXKGJWUCNN-XGXHKTLJSA-N norethisterone Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 VIKNJXKGJWUCNN-XGXHKTLJSA-N 0.000 claims 1
- 229920000573 polyethylene Polymers 0.000 claims 1
- ZMRUPTIKESYGQW-UHFFFAOYSA-N propranolol hydrochloride Chemical compound [H+].[Cl-].C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 ZMRUPTIKESYGQW-UHFFFAOYSA-N 0.000 claims 1
- RUOJZAUFBMNUDX-UHFFFAOYSA-N propylene carbonate Chemical compound CC1COC(=O)O1 RUOJZAUFBMNUDX-UHFFFAOYSA-N 0.000 claims 1
- 229960003946 selegiline Drugs 0.000 claims 1
- MEZLKOACVSPNER-GFCCVEGCSA-N selegiline Chemical compound C#CCN(C)[C@H](C)CC1=CC=CC=C1 MEZLKOACVSPNER-GFCCVEGCSA-N 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- 229940083542 sodium Drugs 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 229910021653 sulphate ion Inorganic materials 0.000 claims 1
- 239000007921 spray Substances 0.000 abstract description 19
- 239000010408 film Substances 0.000 description 29
- 239000004615 ingredient Substances 0.000 description 17
- 239000000443 aerosol Substances 0.000 description 11
- 150000001875 compounds Chemical class 0.000 description 8
- 235000019441 ethanol Nutrition 0.000 description 8
- 229920003149 Eudragit® E 100 Polymers 0.000 description 7
- 239000004480 active ingredient Substances 0.000 description 7
- NEDGUIRITORSKL-UHFFFAOYSA-N butyl 2-methylprop-2-enoate;2-(dimethylamino)ethyl 2-methylprop-2-enoate;methyl 2-methylprop-2-enoate Chemical compound COC(=O)C(C)=C.CCCCOC(=O)C(C)=C.CN(C)CCOC(=O)C(C)=C NEDGUIRITORSKL-UHFFFAOYSA-N 0.000 description 7
- 229920000642 polymer Polymers 0.000 description 7
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- 230000036556 skin irritation Effects 0.000 description 6
- 231100000475 skin irritation Toxicity 0.000 description 6
- 238000009472 formulation Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- NOOLISFMXDJSKH-KXUCPTDWSA-N (-)-Menthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O NOOLISFMXDJSKH-KXUCPTDWSA-N 0.000 description 4
- 239000008118 PEG 6000 Substances 0.000 description 4
- 229920002584 Polyethylene Glycol 6000 Polymers 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000003623 enhancer Substances 0.000 description 3
- 239000006260 foam Substances 0.000 description 3
- 231100000435 percutaneous penetration Toxicity 0.000 description 3
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 description 2
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 2
- 239000004141 Sodium laurylsulphate Substances 0.000 description 2
- 206010053615 Thermal burn Diseases 0.000 description 2
- 239000000853 adhesive Substances 0.000 description 2
- 230000002421 anti-septic effect Effects 0.000 description 2
- 229940065524 anticholinergics inhalants for obstructive airway diseases Drugs 0.000 description 2
- 239000008135 aqueous vehicle Substances 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 239000000812 cholinergic antagonist Substances 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
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- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- 108091006146 Channels Proteins 0.000 description 1
- 229920003139 Eudragit® L 100 Polymers 0.000 description 1
- 229920003151 Eudragit® RL polymer Polymers 0.000 description 1
- 229920003152 Eudragit® RS polymer Polymers 0.000 description 1
- 229920003141 Eudragit® S 100 Polymers 0.000 description 1
- NMJREATYWWNIKX-UHFFFAOYSA-N GnRH Chemical class C1CCC(C(=O)NCC(N)=O)N1C(=O)C(CC(C)C)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)CNC(=O)C(NC(=O)C(CO)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C(CC=1NC=NC=1)NC(=O)C1NC(=O)CC1)CC1=CC=C(O)C=C1 NMJREATYWWNIKX-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 1
- 230000037374 absorbed through the skin Effects 0.000 description 1
- 229940081735 acetylcellulose Drugs 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 235000013877 carbamide Nutrition 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 239000006059 cover glass Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 229940075557 diethylene glycol monoethyl ether Drugs 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000003467 diminishing effect Effects 0.000 description 1
- 229960004667 ethyl cellulose Drugs 0.000 description 1
- FSXVSUSRJXIJHB-UHFFFAOYSA-M ethyl prop-2-enoate;methyl 2-methylprop-2-enoate;trimethyl-[2-(2-methylprop-2-enoyloxy)ethyl]azanium;chloride Chemical compound [Cl-].CCOC(=O)C=C.COC(=O)C(C)=C.CC(=C)C(=O)OCC[N+](C)(C)C FSXVSUSRJXIJHB-UHFFFAOYSA-M 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 229940071826 hydroxyethyl cellulose Drugs 0.000 description 1
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 125000005395 methacrylic acid group Chemical group 0.000 description 1
- 229960002532 methamphetamine hydrochloride Drugs 0.000 description 1
- 229940032007 methylethyl ketone Drugs 0.000 description 1
- 229960001785 mirtazapine Drugs 0.000 description 1
- RONZAEMNMFQXRA-UHFFFAOYSA-N mirtazapine Chemical compound C1C2=CC=CN=C2N2CCN(C)CC2C2=CC=CC=C21 RONZAEMNMFQXRA-UHFFFAOYSA-N 0.000 description 1
- DNKKLDKIFMDAPT-UHFFFAOYSA-N n,n-dimethylmethanamine;2-methylprop-2-enoic acid Chemical compound CN(C)C.CC(=C)C(O)=O.CC(=C)C(O)=O DNKKLDKIFMDAPT-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229950000516 padimate Drugs 0.000 description 1
- LXTZRIBXKVRLOA-UHFFFAOYSA-N padimate a Chemical compound CCCCCOC(=O)C1=CC=C(N(C)C)C=C1 LXTZRIBXKVRLOA-UHFFFAOYSA-N 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 239000002985 plastic film Substances 0.000 description 1
- 229920006255 plastic film Polymers 0.000 description 1
- 229940113116 polyethylene glycol 1000 Drugs 0.000 description 1
- 229940075065 polyvinyl acetate Drugs 0.000 description 1
- 229940068984 polyvinyl alcohol Drugs 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 229920006316 polyvinylpyrrolidine Polymers 0.000 description 1
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- IYETZZCWLLUHIJ-UTONKHPSSA-N selegiline hydrochloride Chemical compound [Cl-].C#CC[NH+](C)[C@H](C)CC1=CC=CC=C1 IYETZZCWLLUHIJ-UTONKHPSSA-N 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/12—Aerosols; Foams
-
- 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
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7015—Drug-containing film-forming compositions, e.g. spray-on
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
- A61L2/0005—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts
- A61L2/0082—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts using chemical substances
Definitions
- This invention relates to compositions for topical application of pharmaceutical compounds. Specifically, the invention relates to topical medicinal spray compositions, their use and films formed upon use. The compositions may be used to treat a variety of disorders.
- British Patent Specification No. 1,372,721 discloses a container of antiseptic for the topical treatment of bums and scalds, containing a topically acceptable antiseptic active agent against Pseudomonas aeruginosa, a pressuring agent and at least one surfactant admixed with water.
- the container comprises an outlet, and valve means operable to allow discharge of the contents of the container through the outlet in the form of a foam which is effective in the control of Pseudomonas aeruginosa at the site of a burn or scald.
- 4,534,958 describes and claims “a sprayable aerosol foam treatment composition which is a liquid in the aerosol container and forms a gel upon application to the skin”.
- the composition in U.S. Pat. No. 4,534,958 comprises water, propellant, volatile solvent, a polyoxyethylene copolymer whose function is not described, and optionally a burn treatment agent and one or more adjuvants.
- the composition is used “for treating living skin”.
- the invention provides advantages not previously realized. Specifically, the invention provides a composition for the topical application of pharmaceutical compounds without causing occlusion problems or skin irritation. Moreover, the inventive compositions remove the need for an adhesive patch. The invention further provides a topically applied composition that may remain as a breathable film on the skin for an extended period of time.
- This invention relates to a topical spray composition which can be sprayed onto the skin to form a breathable film or patch, which remains stable and in place over a period of days. In this way, a medicament can be delivered transdermally over a period of time. Since the film is non-occlusive, the problem of local skin irritation associated with transdermal patches is substantially reduced.
- the invention provides a composition for topical application of one or more medicaments, comprising at least one medicament for systemic or topical availability, at least one film former, and one or more vehicles.
- the composition contains preferably up to about 30% of the at least one medicament, more preferably up to about 10% of the at least one medicament and most preferably up to about 5% of the at least one medicament.
- the composition may further comprise one or more additional components selected from the group consisting of permeation enhancers, solubilizers, plasticizers, and water soluble additives, including humectants.
- Medicaments in the composition may be present in a form that is solubilized or suspended. After application, the medicaments may be locally or transdermlly available and may be released from the composition.
- a wide range of medicaments for human or veterinary use may be used in the composition and the medicament may be present in chiral form.
- the compositions are preferably in a form suitable for application by spraying from an aerosol or pump spray container.
- the invention further provides a stable, breathable film formed by applying the inventive compositions.
- the film is preferably formed over a fixed surface area.
- the fixed surface area is preferably less than about 50 cm 2 and more preferably from about 10 cm 2 to about 25 cm 2 .
- Medicaments of the composition may be locally or transdermlly available for release from the film.
- the invention comprises a method of using the inventive compositions pursuant to which a metered dose of the composition is dispensed onto an intended application site.
- the intended application site is preferably skin, and the metered dose is preferably applied over a fixed surface area.
- the fixed surface area is preferably less than about 50 cm 2 and more preferably from about 10 cm 2 to about 25 cm 2 .
- the metered dose of the composition is preferably dispensed by spraying the composition from a pump or aerosol spray dispenser.
- the composition forms a stable, breathable film on the intended application site after dispensing.
- “Breathable film” refers to a film formed on the surface of the skin that does not interfere with perspiration, respiration and other metabolic activities of the skin.
- “Film-formers” refers to compounds, preferably polymers, that form stable films on a surface when applied.
- a film is stable if it is resistant to removal by rubbing for an extended period of time.
- the extended period of time is preferably at least about 24 hours and most preferably from about 1 day to about 5 days.
- Topical application refers to being applied to a surface such as skin.
- Topicically active refers to the composition or medicament for topical application which treats predominately the surface on which it is applied.
- “Percutaneous penetration” or “transdermally available” means that the medicament of the composition is absorbed through skin when applied topically. Typically, although not necessarily, the medicament will then be distributed throughout the body resulting in systemic action as opposed to being only locally active.
- Permeation Enhancer refers to a component used to enhance the penetration rate of drugs through the skin, preferably by temporarily diminishing the impermeability of the skin. Permeation enhancers have also been called “accelerants” and “sorption promoters.” Examples of permeation enhancers include lipophilic solvents, surfactants, menthol, fatty acid esters and polyhydric alcohols.
- Plasticizer refers to a component that aids a composition in forming a flexible, adherent film on the skin.
- plasticizers include citrate esters, dimethyl isosorbide, castor oil, propylene glycol and polyethylene glycol.
- solubilizer refers to components that aid in the dissolution or dispersement of the drug in the formulation.
- solubilizers include acrylate and methacrylate ester polymers and copolymers, surfactants, polyhydric alcohols, Vitamin E, Vitamin E TPGS and labrasol.
- the present invention includes a topical, medicinal spray composition
- a topical, medicinal spray composition comprising a drug or combination of drugs as a solution or suspension in a vehicle optionally containing a polymer or combination of polymers which, when sprayed on the surface of the skin, forms a film on the skin.
- the compositions of the invention preferably comprise up to about 30% of at least one medicament (e.g., 0.0001% to about 30%), more preferably up to about 10% of at least one medicament (e.g., 0.0001% to about 10%) and most preferably up to about 5% of at least one medicament (e.g., 0.0001% to about 5%) dissolved or suspended in one or more vehicles which comprise up to 90% of the composition (e.g., 0.0001% to about 90%).
- the composition may further contain one or more film former, solubilizer, permeation enhancer and plasticizer.
- the composition may contain one or more of these additives in amounts of up to about 10% film-former (e.g., 0.0001% to about 10%), up to about 10% solubilizer (e.g., 0.0001% to about 10%), up to about 8% permeation enhancer (e.g., 0.0001% to about 8%), and up to about 10% plasticizer (e.g., 0.0001% to about 10%).
- the inventive composition may be sprayed on a topical site to form a stable, breathable film on the site, from which film the medicaments act locally on the surface or are transdermally available.
- the composition further comprises up to about 7% (w/w) of one or more water-soluble additives (e.g., 0.0001% to about 7%).
- the drug or combination of drugs so deposited in the matrix of the film-former may remain solubilized or suspended.
- the exact formulation of the composition may vary depending on the nature of the particular medicament used (for example, the solubility profile) and the release profile desired.
- the compositions can be dispensed from any dispenser, preferably a dispenser which provides the composition as a spray, and may be used for systemic action or topical action.
- the drug from the composition may be released over a period of time or immediately.
- compositions of the present invention are preferably applied in a metered dose over a predetermined surface area. Accordingly, the present invention may also provide for the administration of the composition by spraying the composition from a dispenser. The invention further provides a method for applying the composition and the resultant film.
- the composition is dispensed from a pump dispenser or from an aerosol dispenser.
- the composition additionally comprises from about 10% to 90% of propellant in order to provide a suitable pressure within the aerosol dispenser.
- propellant is not required for compositions dispensed from a pump dispenser.
- such compositions may also comprise from about 10% to 90% of a propellant which is liquid at room temperature, for example, trichloromonofluoromethane (P11).
- the invention also provides a method of preparing a pump dispenser containing the spray composition of the invention comprising mixing the ingredients of the composition with or without liquid propellant and placing the mixed ingredients in a pump dispenser.
- the invention provides a method of preparing an aerosol dispenser containing the spray composition of the invention comprising mixing the ingredients of the composition without propellant and charging the mixture together with propellant into an aerosol dispenser.
- the composition is preferably dispensed from the chosen dispenser in a metered dose.
- the medicament can be any medicinal compound in the salt or base form or a combination of compounds which is stable on mixing with the other ingredients of the composition and effective on topical administration.
- the medicament is preferably a drug which is an anti-emetic, an anti-anginal, an anti-inflammatory, a steroid, a steroid hormone, a bronchodilator or a drug used to treat osteoporosis.
- Additional preferred medicaments include drugs used to treat incontinence, antidepressants/anxiolytics, antimigraine agents, agents used in smoking cessation therapy, antidiarrheals, anticholinergics, anticonvulsants, drugs for mood disorders/obsessive compulsive disorder, ACE inhibitors, calcium channel blockers, antihypertensives/diuretics, antiobesity drugs, hormonal peptides and analogues, drugs for benign prostatic hyperplasia/urinary retention and erectile dysfunctions, antiparkinson agents such as dopamine agonists and MAO inhibitors, drugs for sleep disorders and antidiabetic agents.
- drugs used to treat incontinence include drugs used to treat incontinence, antidepressants/anxiolytics, antimigraine agents, agents used in smoking cessation therapy, antidiarrheals, anticholinergics, anticonvulsants, drugs for mood disorders/obsessive compulsive disorder,
- Preferred anti-emetic is scopolamine.
- Preferred anti-anginals include nitroglycerine, clonidine, isosorbide dinitrate, propanolol HCl, timolol maleate, clonazepam and verapamil.
- Preferred anti-inflammatory drugs include diclofenac sodium, naproxen sodium, ibuprofen, ketoprofen, indomethacin, piroxicam, ketorolac, tromethamine and nimesulide.
- Preferred steroids include hydrocortisone and esters thereof, dexamethasone, fluocinolone acetonide and betamethasone and salts thereof.
- Preferred hormonal steroids include estradiol or noethisterone and their pharmaceutically acceptable salts or a combination thereof, testosterone or progesterone.
- Preferred bronchodilators include salbutamol and salts thereof, bambuterol, salmeterol xinafoate, fluticasone propionate, mometasone furoate, budesonide, beclomethasone dipropionate, sodium cromoglycate and isoprenaline sulphate.
- Preferred drugs used in case of osteoporosis include alendronic acid, pamidronic acid, etidronic acid and their pharmaceutically acceptable salts.
- Preferred drugs used to treat incontinence include vasopressin and oxybutynin.
- Preferred antidepressants/anxiolytics include imipramine, mirtazapine and desipramine.
- Preferred antimigraine agents include naratriptan, zolmitriptan and sumatriptan.
- One preferred antidiarrheal is loperamide.
- One preferred antiulcerant is misoprostol.
- Preferred anticholinergics include hyoscyamine, atropine and trihexyphenidyl.
- Preferred anticonvulsants include lorazepam, diazepam and tiagabine.
- Preferred drugs for antimood disorders/obsessive compulsive disorder include fluoxetine and paroxetine.
- Preferred ACE inhibitors include lisinopril, trandolapril and captopril.
- Preferred calcium channel blockers include amlodipine and felodipine.
- Preferred antihypertensives/diuretics include prazosin and amiloride.
- Preferred antiobesity drugs include methamphetamine and sibutramine hydrochloride.
- Preferred hormonal peptides and analogues include GnRH analogues such as nafarelin, leuprolide acetate, insulin and growth hormone and analogues thereof.
- Preferred drugs for benign prostatic hyperplasia/urinary retention include doxazosin, tamsulosin, terazosin and finasteride.
- Preferred drugs for erectile dysfunction include alprostadil and sildenafil citrate.
- Preferred antiparkinson agents include dopamine agonists such as bromocriptine and cabergoline and MAO inhibitors such as selegiline HCl.
- One preferred agent for sleep disorders is melatonin.
- Preferred antidiabetic agents include first and second generation sulphonyl ureas such as glimepiride, rosiglitazone, glyburide and glipizide. The chiral forms of all the drugs mentioned above, as well as achiral forms, can be used to make the topical spray composition of the present invention.
- the film-formers preferably include acrylic polymers or copolymers, including methacrylic polymers and copolymers.
- Preferred film-formers include a non-ionic copolymer of methyl methacrylate and butyl methacrylate (Plastoid B®), a copolymer of dimethylamine ethyl methacrylate and a neutral methacrylic acid ester (Eudragit E100®), ammonio methacrylate copolymer type B (Eudragit RS®, USP/NF), ammonio methacrylate copolymer type A (Eudragit RL®, USP/NF), methacrylic acid copolymer type A (Eudragit L100®, USP/NF), methacrylic acid copolymer type B (Eudragit S100® USP/NF), polyvinyl acetate, cellulose acetate, polyvinyl alcohol, povidone, povidone vinyl acetate, hydroxypropyl
- the breathability of the film is achieved by the absence of any occlusive backing membrane together with the generally hydrophilic properties of the film-forming polymer(s). These polymers can partially dissolve on exposure to moisture (from the skin or air), the dissolution resulting in the formation of a porous film. This porosity can be enhanced by including additional water-soluble additives, such as those detailed below.
- Preferred solubilizers include a copolymer of dimethylamine ethyl methacrylate and a neutral methacrylic acid ester (Eudragit E100®, USP/NF); surfactants, for example, sodium lauryl sulphate; polyhydric alcohols, for example, propylene glycol or polyethylene glycol; vitamin E, vitamin E TPGS (tocopheryl polyethylene glycol 1000 succinate) and labrasol; or any two or more of the above in combination.
- surfactants for example, sodium lauryl sulphate
- polyhydric alcohols for example, propylene glycol or polyethylene glycol
- vitamin E vitamin E TPGS (tocopheryl polyethylene glycol 1000 succinate) and labrasol
- labrasol any two or more of the above in combination.
- the solubilizer is a copolymer of dimethylamine ethyl methacrylate and a neutral methacrylic acid ester (Eudragit E100®) in combination with, a non-ionic copolymer of methyl methacrylate and butyl methacrylate (Plastoid B®).
- the solubilizers serve to dissolve the drug in the chosen vehicle. Many of the solubilizers also enhance percutaneous penetration of drug and/or act as humectants.
- Preferred plasticizers include triethyl citrate, dimethyl isosorbide, acetyltributyl citrate, castor oil, propylene glycol, and polyethylene glycol, or any two or more of the above in combination.
- the permeation enhancer is preferably a lipophilic solvent, for example, dimethyl sulfoxide, dimethyl formamide or isopropyl myristate; a surfactant, for example, Tweens or sodium lauryl sulfate; menthol; oleic acid, octyl dimethyl para-amino benzoic acid (Padimate 0); mixed esters of capric and caprylic acid; or a polyhydric alcohol, for example, propylene glycol or diethylene glycol monoethyl ether EP (transcutol); or any two or more of the above in combination.
- a lipophilic solvent for example, dimethyl sulfoxide, dimethyl formamide or isopropyl myristate
- a surfactant for example, Tweens or sodium lauryl sulfate
- menthol oleic acid, octyl dimethyl para-amino benzoic acid (Padimate 0)
- the vehicle can be water or a non-aqueous solvent.
- Preferred nonaqueous vehicles include acetone, isopropyl alcohol, methylene chloride, methyl-ethyl-ketone, absolute alcohol, ethyl acetate and trichloromonofluoromethane (P11), methylene dimethyl ether or any two or more of the above in combination.
- the aqueous or non-aqueous vehicle may additionally comprise (weight/weight of vehicle) up to 20% of one or more humectants.
- Preferred humectants include polyhydric alcohols and polyvinyl pyrrolidone.
- Preferred polyhydric alcohols are propylene glycol, butylene glycol, polyethylene glycol, glycerol and sorbitol.
- the water-soluble additive is preferably propylene glycol, sodium lauryl sulphate, one or more polaxomers, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, cetomacrogol, polyethylene glycol or transcutol, or any two or more of the above in combination.
- the vehicle When the composition is dispensed as an aerosol, the vehicle partly comprises a propellant in an amount to provide from about 10% to about 90% (w/w) of the composition.
- the propellant can be any pharmaceutically acceptable propellant which provides a suitable pressure within an aerosol dispenser, preferably a pressure of from about 20 p.s.i.g. to about 130 p.s.i.g.
- Preferred propellants include hydrocarbons, for example, propane, butane, isobutane, or dimethylether; hydrofluorocarbons and hydrochlorofluorocarbons, for example, dichlorodifluoromethane (P12), trichloromonofluoromethane (P11), dichlorofluoroethane, monochlorodifluoromethane (P22), dichlorotetrafluoroethane (P114), difluoroethane (P152a), tetrafluoroethane (134a), heptafluoropropane (P227b); or compressed gases, for example, nitrogen or carbon dioxide.
- hydrocarbons for example, propane, butane, isobutane, or dimethylether
- hydrofluorocarbons and hydrochlorofluorocarbons for example, dichlorodifluoromethane (P12), trichloromonofluoromethane (P11), dichloroflu
- compositions of the present invention are quick drying, non-occlusive formulations which cause marked enhancement of the skin permeation of the drug both in vitro and in vivo when compared with existing transdermal patches. They offer the advantages of lower skin irritation, greater ease of use, increased dosage flexibility and a simpler method of manufacture when compared to existing transdermal patches.
- the present compositions are a significant advance over conventional medicinal aerosol compositions, since they permit the application of a medicament by a method whereby no physical contact on the area of application is required, except by the film-forming spray itself.
- the topical films formed by the present compositions show excellent stability and peelability and can be easily removed from the site of application by washing with water.
- compositions are generally prepared by mixing the ingredients, without liquefied propellant, at a temperature of from 0° C. to 100° C. and at ambient pressure. If propellant is to be added, the resulting mixture is then charged with the liquefied propellant into an aerosol dispenser to achieve the final composition. Mixing is preferably carried out at a temperature of from 10° C. to 25° C. Alternatively, the mixed composition is placed in a pump dispenser, for example, a metered dose pump, which dispenses the composition typically without liquefied propellant since a pressurized atmosphere is not required. Propellant which is liquid at room temperature may, however, be included in a pump dispenser composition as part of the aqueous vehicle. The composition so prepared is sprayed from the dispenser onto a topical site, at which site it forms a stable, plastic film or patch.
- the aerosol dispenser is preferably a conventional aerosol can having a conventional metered spray aerosol valve.
- the pump dispenser is preferably a conventional can or bottle having a conventional metered spray pump.
- the aerosol dispenser has an all position valve having a shroud that permits spraying when the dispenser is held at any angle. In this way, horizontal bottom surfaces, as well as horizontal top surfaces and vertical surfaces, can be sprayed.
- the valve actuator can be any actuator which produces a spray and not a foam at the nozzle.
- a preferred valve actuator is a mechanical breakup actuator, which employs mechanical forces rather than expansion and evaporation of the propellant to produce a spray.
- a typical mechanical breakup actuator has a conical or cylindrical swirl chamber with an inlet channel oriented perpendicular to the axis thereof.
- This structure imparts a swirling motion to the aerosol mixture upon discharge.
- the swirling motion occurs around the axis of the swirl chamber forming a thin conical film of discharged mixture, which breaks into droplets as it leaves the swirl chamber and travels in the direction of the axis thereof.
- the result is a fine, soft, dispersed spray which can be easily controlled to produce a stable thin film of even thickness completely contacting the application site.
- the dispenser In dispensing a composition of the invention, the dispenser is typically held about 1 to 2 inches (2.5 to 5 cm) from the application site and produces a film of even thickness.
- the dispensers used in the present invention are preferably compact units. They can be conveniently used for quick and easy application of a medicament over a large surface area.
- the composition is preferably applied over a fixed surface area.
- the fixed surface area is not more than 50 cm 2 , and is more preferably from 10 cm 2 to 25 cm 2 .
- composition according to the present invention suitable for use in an aerosol dispenser can be prepared as follows:
- Examples 1 and 2 below represent partly generalized formulas which can be used with any suitable medicament to prepare compositions according to the present invention for use in an aerosol dispenser.
- compositions for use in an aerosol dispenser are set forth in Examples 3 through 5.
- composition according to the present invention suitable for use in a pump dispenser, the general method set forth above for an aerosol dispenser can be used, except that it is not necessary to charge the pump dispenser with liquefied propellant to provide a pressurized atmosphere.
- the mixture itself may contain propellant which is liquid at room temperature as part of the vehicle.
- Examples 6 through 9 represent partly generalized formulas which can be used with any suitable medicament to prepare compositions according to the present invention for use in a pump dispenser.
- compositions which can be used in a pump dispenser are set forth in Examples 10 through 12.
- Eudragit E 100 is a self-adhesive, hydrophilic matrix system. It also acts as a solubilizer for the drug Estradiol.
- Plastoid B is a film-former. When used together, Eudragit E 100 and Plastoid B give better peelability and water washability than when either is used alone.
- Acetone is a volatile, quick-drying, non-occlusive vehicle which helps to dispense the contents of the spray over a large surface area.
- Propylene glycol acts as a humectant to prevent the excessive drying of the application site after application of the medicament. It also acts as a plasticizer for the film formed after application. Propylene glycol additionally acts as a solubilizer for the drug and a permeation enhancer.
- Sodium lauryl sulfate acts as a solubilizer for the drug
- Propellant is necessary for developing proper pressure within an aerosol container and for expulsion of the composition when the valve is open. It is also responsible, together with the valve, for dispensing the product as a fine spray.
- the preferred propellants are very stable compounds and relatively non-toxic, inert and non-flammable.
- compositions in the above examples were discharged from the dispenser as a fine, soft dispersed spray which could be easily controlled to produce a stable thin film of even thickness on a target surface, for example, a laboratory cover glass.
- the films have been observed to last for at least 24 hours.
- concentrations of the film-formers in the composition can be varied as required to obtain a patch which can deliver the drug in a sustained manner for a period of up to 1 to 5 days.
- the film is easily removable from the application site by water in preparation for reapplication of the film or other treatment.
Abstract
A topical, medicinal spray composition is provided comprising a drug or combination of drugs in a carrier which, when sprayed on a surface, forms a film. The composition comprises at least one medicament, at least one film former and at least one vehicle. The composition of the invention may further comprise at least one permeation enhancer, at least one solubilizer, at least one plasticizer, and at least one water soluble additive. A metered dose of the composition can be sprayed on a topical site to form a stable, breathable film, preferably over a fixed surface area. A wide range of medicaments for human and veterinary use may be present that act locally or transdermally.
Description
- This application is a continuation of U.S. application Ser. No. 09/503,843, filed Feb. 15, 2000, which claims priority to Indian Patent Application Nos. 382/BOM/99, filed May 20, 1999; 582/BOM/99, filed Aug. 17, 1999; 43/BOM/2000, filed Jan. 13, 2000; and 44/BOM/2000, Jan. 13, 2000, eacjh of which is incorporated herein by reference in its entirety.
- 1. Field of the Invention
- This invention relates to compositions for topical application of pharmaceutical compounds. Specifically, the invention relates to topical medicinal spray compositions, their use and films formed upon use. The compositions may be used to treat a variety of disorders.
- 2. Background of the Invention
- Many delivery systems for the topical application of pharmaceutical compounds are currently available and include lotions, creams, gels, ointments, transdermal patches and sprays. The choice of delivery system usually depends upon the desired pharmacokinetic profile of the drug, for example, whether immediate or sustained release is required. Many of these systems suffer from occlusion problems and may cause skin irritation. For example, many compounds, including hormonal drugs, are conventionally delivered using a transdermal patch. These patches comprise an occlusive backing membrane which often results in local skin irritation. A further disadvantage of transdermal patches is that percutaneous penetration of the drug is often poor.
- The problem of skin irritation associated with transdermal patches is not as pronounced when topical spray formulations are used. For example, British Patent Specification No. 1,372,721 discloses a container of antiseptic for the topical treatment of bums and scalds, containing a topically acceptable antiseptic active agent againstPseudomonas aeruginosa, a pressuring agent and at least one surfactant admixed with water. The container comprises an outlet, and valve means operable to allow discharge of the contents of the container through the outlet in the form of a foam which is effective in the control of Pseudomonas aeruginosa at the site of a burn or scald. U.S. Pat. No. 4,534,958 describes and claims “a sprayable aerosol foam treatment composition which is a liquid in the aerosol container and forms a gel upon application to the skin”. The composition in U.S. Pat. No. 4,534,958 comprises water, propellant, volatile solvent, a polyoxyethylene copolymer whose function is not described, and optionally a burn treatment agent and one or more adjuvants. The composition is used “for treating living skin”.
- However, conventional topical spray formulations tend to remain at the application site for only a short time. For example, they are easily rubbed off. As a result, the medicament to be absorbed through the skin is only available transiently. By contrast, medicament in a transdermal patch is potentially available for as long as the patch remains in place.
- This invention provides advantages not previously realized. Specifically, the invention provides a composition for the topical application of pharmaceutical compounds without causing occlusion problems or skin irritation. Moreover, the inventive compositions remove the need for an adhesive patch. The invention further provides a topically applied composition that may remain as a breathable film on the skin for an extended period of time.
- Through this invention, the advantages offered by transdermal patches and topical sprays have been combined, while the disadvantages associated with each have been minimized. This invention relates to a topical spray composition which can be sprayed onto the skin to form a breathable film or patch, which remains stable and in place over a period of days. In this way, a medicament can be delivered transdermally over a period of time. Since the film is non-occlusive, the problem of local skin irritation associated with transdermal patches is substantially reduced.
- The invention provides a composition for topical application of one or more medicaments, comprising at least one medicament for systemic or topical availability, at least one film former, and one or more vehicles. The composition contains preferably up to about 30% of the at least one medicament, more preferably up to about 10% of the at least one medicament and most preferably up to about 5% of the at least one medicament. The composition may further comprise one or more additional components selected from the group consisting of permeation enhancers, solubilizers, plasticizers, and water soluble additives, including humectants. Medicaments in the composition may be present in a form that is solubilized or suspended. After application, the medicaments may be locally or transdermlly available and may be released from the composition. A wide range of medicaments for human or veterinary use may be used in the composition and the medicament may be present in chiral form. The compositions are preferably in a form suitable for application by spraying from an aerosol or pump spray container.
- The invention further provides a stable, breathable film formed by applying the inventive compositions. The film is preferably formed over a fixed surface area. The fixed surface area is preferably less than about 50 cm2 and more preferably from about 10 cm2 to about 25 cm2. Medicaments of the composition may be locally or transdermlly available for release from the film.
- Moreover, the invention comprises a method of using the inventive compositions pursuant to which a metered dose of the composition is dispensed onto an intended application site. The intended application site is preferably skin, and the metered dose is preferably applied over a fixed surface area. The fixed surface area is preferably less than about 50 cm2 and more preferably from about 10 cm2 to about 25 cm2. The metered dose of the composition is preferably dispensed by spraying the composition from a pump or aerosol spray dispenser. In one embodiment, the composition forms a stable, breathable film on the intended application site after dispensing.
- The above objectives and advantages of the invention are illustrative, and not exhaustive, of those which can be achieved by the invention. The examples presented herein are non-limiting.
- In describing the invention, the following definitions are applicable throughout.
- “Breathable film” refers to a film formed on the surface of the skin that does not interfere with perspiration, respiration and other metabolic activities of the skin.
- “Film-formers” refers to compounds, preferably polymers, that form stable films on a surface when applied. Within the meaning of the present invention, a film is stable if it is resistant to removal by rubbing for an extended period of time. The extended period of time is preferably at least about 24 hours and most preferably from about 1 day to about 5 days.
- “Topical application” refers to being applied to a surface such as skin.
- “Topically active” refers to the composition or medicament for topical application which treats predominately the surface on which it is applied.
- “Percutaneous penetration” or “transdermally available” means that the medicament of the composition is absorbed through skin when applied topically. Typically, although not necessarily, the medicament will then be distributed throughout the body resulting in systemic action as opposed to being only locally active.
- “Permeation Enhancer” refers to a component used to enhance the penetration rate of drugs through the skin, preferably by temporarily diminishing the impermeability of the skin. Permeation enhancers have also been called “accelerants” and “sorption promoters.” Examples of permeation enhancers include lipophilic solvents, surfactants, menthol, fatty acid esters and polyhydric alcohols.
- “Plasticizer” refers to a component that aids a composition in forming a flexible, adherent film on the skin. Examples of plasticizers include citrate esters, dimethyl isosorbide, castor oil, propylene glycol and polyethylene glycol.
- “Solubilizer” refers to components that aid in the dissolution or dispersement of the drug in the formulation. Examples of solubilizers include acrylate and methacrylate ester polymers and copolymers, surfactants, polyhydric alcohols, Vitamin E, Vitamin E TPGS and labrasol.
- The present invention includes a topical, medicinal spray composition comprising a drug or combination of drugs as a solution or suspension in a vehicle optionally containing a polymer or combination of polymers which, when sprayed on the surface of the skin, forms a film on the skin. The compositions of the invention preferably comprise up to about 30% of at least one medicament (e.g., 0.0001% to about 30%), more preferably up to about 10% of at least one medicament (e.g., 0.0001% to about 10%) and most preferably up to about 5% of at least one medicament (e.g., 0.0001% to about 5%) dissolved or suspended in one or more vehicles which comprise up to 90% of the composition (e.g., 0.0001% to about 90%). The composition may further contain one or more film former, solubilizer, permeation enhancer and plasticizer. The composition may contain one or more of these additives in amounts of up to about 10% film-former (e.g., 0.0001% to about 10%), up to about 10% solubilizer (e.g., 0.0001% to about 10%), up to about 8% permeation enhancer (e.g., 0.0001% to about 8%), and up to about 10% plasticizer (e.g., 0.0001% to about 10%). The inventive composition may be sprayed on a topical site to form a stable, breathable film on the site, from which film the medicaments act locally on the surface or are transdermally available. Preferably, the composition further comprises up to about 7% (w/w) of one or more water-soluble additives (e.g., 0.0001% to about 7%). The drug or combination of drugs so deposited in the matrix of the film-former may remain solubilized or suspended. The exact formulation of the composition may vary depending on the nature of the particular medicament used (for example, the solubility profile) and the release profile desired. The compositions can be dispensed from any dispenser, preferably a dispenser which provides the composition as a spray, and may be used for systemic action or topical action. The drug from the composition may be released over a period of time or immediately.
- The compositions of the present invention are preferably applied in a metered dose over a predetermined surface area. Accordingly, the present invention may also provide for the administration of the composition by spraying the composition from a dispenser. The invention further provides a method for applying the composition and the resultant film.
- Preferably, the composition is dispensed from a pump dispenser or from an aerosol dispenser. In the latter case, the composition additionally comprises from about 10% to 90% of propellant in order to provide a suitable pressure within the aerosol dispenser. Generally, propellant is not required for compositions dispensed from a pump dispenser. However, if desired, such compositions may also comprise from about 10% to 90% of a propellant which is liquid at room temperature, for example, trichloromonofluoromethane (P11).
- The invention also provides a method of preparing a pump dispenser containing the spray composition of the invention comprising mixing the ingredients of the composition with or without liquid propellant and placing the mixed ingredients in a pump dispenser.
- In addition, the invention provides a method of preparing an aerosol dispenser containing the spray composition of the invention comprising mixing the ingredients of the composition without propellant and charging the mixture together with propellant into an aerosol dispenser. The composition is preferably dispensed from the chosen dispenser in a metered dose.
- The medicament can be any medicinal compound in the salt or base form or a combination of compounds which is stable on mixing with the other ingredients of the composition and effective on topical administration. The medicament is preferably a drug which is an anti-emetic, an anti-anginal, an anti-inflammatory, a steroid, a steroid hormone, a bronchodilator or a drug used to treat osteoporosis. Additional preferred medicaments include drugs used to treat incontinence, antidepressants/anxiolytics, antimigraine agents, agents used in smoking cessation therapy, antidiarrheals, anticholinergics, anticonvulsants, drugs for mood disorders/obsessive compulsive disorder, ACE inhibitors, calcium channel blockers, antihypertensives/diuretics, antiobesity drugs, hormonal peptides and analogues, drugs for benign prostatic hyperplasia/urinary retention and erectile dysfunctions, antiparkinson agents such as dopamine agonists and MAO inhibitors, drugs for sleep disorders and antidiabetic agents.
- One preferred anti-emetic is scopolamine. Preferred anti-anginals include nitroglycerine, clonidine, isosorbide dinitrate, propanolol HCl, timolol maleate, clonazepam and verapamil. Preferred anti-inflammatory drugs include diclofenac sodium, naproxen sodium, ibuprofen, ketoprofen, indomethacin, piroxicam, ketorolac, tromethamine and nimesulide. Preferred steroids include hydrocortisone and esters thereof, dexamethasone, fluocinolone acetonide and betamethasone and salts thereof. Preferred hormonal steroids include estradiol or noethisterone and their pharmaceutically acceptable salts or a combination thereof, testosterone or progesterone. Preferred bronchodilators include salbutamol and salts thereof, bambuterol, salmeterol xinafoate, fluticasone propionate, mometasone furoate, budesonide, beclomethasone dipropionate, sodium cromoglycate and isoprenaline sulphate. Preferred drugs used in case of osteoporosis include alendronic acid, pamidronic acid, etidronic acid and their pharmaceutically acceptable salts. Preferred drugs used to treat incontinence include vasopressin and oxybutynin. Preferred antidepressants/anxiolytics include imipramine, mirtazapine and desipramine. Preferred antimigraine agents include naratriptan, zolmitriptan and sumatriptan. One preferred antidiarrheal is loperamide. One preferred antiulcerant is misoprostol. Preferred anticholinergics include hyoscyamine, atropine and trihexyphenidyl. Preferred anticonvulsants include lorazepam, diazepam and tiagabine. Preferred drugs for antimood disorders/obsessive compulsive disorder include fluoxetine and paroxetine. Preferred ACE inhibitors include lisinopril, trandolapril and captopril. Preferred calcium channel blockers include amlodipine and felodipine. Preferred antihypertensives/diuretics include prazosin and amiloride. Preferred antiobesity drugs include methamphetamine and sibutramine hydrochloride. Preferred hormonal peptides and analogues include GnRH analogues such as nafarelin, leuprolide acetate, insulin and growth hormone and analogues thereof. Preferred drugs for benign prostatic hyperplasia/urinary retention include doxazosin, tamsulosin, terazosin and finasteride. Preferred drugs for erectile dysfunction include alprostadil and sildenafil citrate. Preferred antiparkinson agents include dopamine agonists such as bromocriptine and cabergoline and MAO inhibitors such as selegiline HCl. One preferred agent for sleep disorders is melatonin. Preferred antidiabetic agents include first and second generation sulphonyl ureas such as glimepiride, rosiglitazone, glyburide and glipizide. The chiral forms of all the drugs mentioned above, as well as achiral forms, can be used to make the topical spray composition of the present invention.
- The film-formers preferably include acrylic polymers or copolymers, including methacrylic polymers and copolymers. Preferred film-formers include a non-ionic copolymer of methyl methacrylate and butyl methacrylate (Plastoid B®), a copolymer of dimethylamine ethyl methacrylate and a neutral methacrylic acid ester (Eudragit E100®), ammonio methacrylate copolymer type B (Eudragit RS®, USP/NF), ammonio methacrylate copolymer type A (Eudragit RL®, USP/NF), methacrylic acid copolymer type A (Eudragit L100®, USP/NF), methacrylic acid copolymer type B (Eudragit S100® USP/NF), polyvinyl acetate, cellulose acetate, polyvinyl alcohol, povidone, povidone vinyl acetate, hydroxypropyl methyl cellulose, hydroxy ethyl cellulose, methyl cellulose and ethyl cellulose.
- The breathability of the film is achieved by the absence of any occlusive backing membrane together with the generally hydrophilic properties of the film-forming polymer(s). These polymers can partially dissolve on exposure to moisture (from the skin or air), the dissolution resulting in the formation of a porous film. This porosity can be enhanced by including additional water-soluble additives, such as those detailed below.
- Preferred solubilizers include a copolymer of dimethylamine ethyl methacrylate and a neutral methacrylic acid ester (Eudragit E100®, USP/NF); surfactants, for example, sodium lauryl sulphate; polyhydric alcohols, for example, propylene glycol or polyethylene glycol; vitamin E, vitamin E TPGS (tocopheryl polyethylene glycol 1000 succinate) and labrasol; or any two or more of the above in combination. Preferably, the solubilizer is a copolymer of dimethylamine ethyl methacrylate and a neutral methacrylic acid ester (Eudragit E100®) in combination with, a non-ionic copolymer of methyl methacrylate and butyl methacrylate (Plastoid B®). The solubilizers serve to dissolve the drug in the chosen vehicle. Many of the solubilizers also enhance percutaneous penetration of drug and/or act as humectants.
- Preferred plasticizers include triethyl citrate, dimethyl isosorbide, acetyltributyl citrate, castor oil, propylene glycol, and polyethylene glycol, or any two or more of the above in combination.
- The permeation enhancer is preferably a lipophilic solvent, for example, dimethyl sulfoxide, dimethyl formamide or isopropyl myristate; a surfactant, for example, Tweens or sodium lauryl sulfate; menthol; oleic acid, octyl dimethyl para-amino benzoic acid (Padimate 0); mixed esters of capric and caprylic acid; or a polyhydric alcohol, for example, propylene glycol or diethylene glycol monoethyl ether EP (transcutol); or any two or more of the above in combination.
- The vehicle can be water or a non-aqueous solvent. Preferred nonaqueous vehicles include acetone, isopropyl alcohol, methylene chloride, methyl-ethyl-ketone, absolute alcohol, ethyl acetate and trichloromonofluoromethane (P11), methylene dimethyl ether or any two or more of the above in combination.
- The aqueous or non-aqueous vehicle may additionally comprise (weight/weight of vehicle) up to 20% of one or more humectants. Preferred humectants include polyhydric alcohols and polyvinyl pyrrolidone. Preferred polyhydric alcohols are propylene glycol, butylene glycol, polyethylene glycol, glycerol and sorbitol.
- The water-soluble additive is preferably propylene glycol, sodium lauryl sulphate, one or more polaxomers, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, cetomacrogol, polyethylene glycol or transcutol, or any two or more of the above in combination.
- When the composition is dispensed as an aerosol, the vehicle partly comprises a propellant in an amount to provide from about 10% to about 90% (w/w) of the composition. The propellant can be any pharmaceutically acceptable propellant which provides a suitable pressure within an aerosol dispenser, preferably a pressure of from about 20 p.s.i.g. to about 130 p.s.i.g. Preferred propellants include hydrocarbons, for example, propane, butane, isobutane, or dimethylether; hydrofluorocarbons and hydrochlorofluorocarbons, for example, dichlorodifluoromethane (P12), trichloromonofluoromethane (P11), dichlorofluoroethane, monochlorodifluoromethane (P22), dichlorotetrafluoroethane (P114), difluoroethane (P152a), tetrafluoroethane (134a), heptafluoropropane (P227b); or compressed gases, for example, nitrogen or carbon dioxide.
- The topical compositions of the present invention are quick drying, non-occlusive formulations which cause marked enhancement of the skin permeation of the drug both in vitro and in vivo when compared with existing transdermal patches. They offer the advantages of lower skin irritation, greater ease of use, increased dosage flexibility and a simpler method of manufacture when compared to existing transdermal patches.
- The present compositions are a significant advance over conventional medicinal aerosol compositions, since they permit the application of a medicament by a method whereby no physical contact on the area of application is required, except by the film-forming spray itself. The topical films formed by the present compositions show excellent stability and peelability and can be easily removed from the site of application by washing with water.
- The compositions are generally prepared by mixing the ingredients, without liquefied propellant, at a temperature of from 0° C. to 100° C. and at ambient pressure. If propellant is to be added, the resulting mixture is then charged with the liquefied propellant into an aerosol dispenser to achieve the final composition. Mixing is preferably carried out at a temperature of from 10° C. to 25° C. Alternatively, the mixed composition is placed in a pump dispenser, for example, a metered dose pump, which dispenses the composition typically without liquefied propellant since a pressurized atmosphere is not required. Propellant which is liquid at room temperature may, however, be included in a pump dispenser composition as part of the aqueous vehicle. The composition so prepared is sprayed from the dispenser onto a topical site, at which site it forms a stable, plastic film or patch.
- The aerosol dispenser is preferably a conventional aerosol can having a conventional metered spray aerosol valve. The pump dispenser is preferably a conventional can or bottle having a conventional metered spray pump. Preferably, the aerosol dispenser has an all position valve having a shroud that permits spraying when the dispenser is held at any angle. In this way, horizontal bottom surfaces, as well as horizontal top surfaces and vertical surfaces, can be sprayed. The valve actuator can be any actuator which produces a spray and not a foam at the nozzle. A preferred valve actuator is a mechanical breakup actuator, which employs mechanical forces rather than expansion and evaporation of the propellant to produce a spray. A typical mechanical breakup actuator has a conical or cylindrical swirl chamber with an inlet channel oriented perpendicular to the axis thereof. This structure imparts a swirling motion to the aerosol mixture upon discharge. The swirling motion occurs around the axis of the swirl chamber forming a thin conical film of discharged mixture, which breaks into droplets as it leaves the swirl chamber and travels in the direction of the axis thereof. The result is a fine, soft, dispersed spray which can be easily controlled to produce a stable thin film of even thickness completely contacting the application site. In dispensing a composition of the invention, the dispenser is typically held about 1 to 2 inches (2.5 to 5 cm) from the application site and produces a film of even thickness. The dispensers used in the present invention are preferably compact units. They can be conveniently used for quick and easy application of a medicament over a large surface area.
- The composition is preferably applied over a fixed surface area. Typically, the fixed surface area is not more than 50 cm2, and is more preferably from 10 cm2 to 25 cm2.
- In general, a composition according to the present invention suitable for use in an aerosol dispenser can be prepared as follows:
- 1. Dissolve the film former in the chosen vehicle with stirring to form a clear solution;
- 2. Dissolve or suspend the active ingredient and solubilizer(s) along with the permeation enhancer, together with any water-soluble additives required, in the solution formed in step 1;
- 3. Add the plasticizer to the solution and fill a conventional aerosol can with the mixture; and
- 4. Charge the filled can with liquefied propellant.
- The following examples illustrate the preparation of compositions according to the present invention.
- Examples 1 and 2 below represent partly generalized formulas which can be used with any suitable medicament to prepare compositions according to the present invention for use in an aerosol dispenser.
-
Ingredients Percent w/w Active ingredient 0.5-10.0 Plastoid B 2.25 Eudragit E 100 0.25 Propylene glycol 3.0 Sodium lauryl sulfate 3.5 Acetone 20 Propellant q.s. Vitamin E 0.1 Transcutol 1.0 -
Ingredients Percent w/w Active ingredient 15 Povidone 3 Povidone VA-64 2 Vitamin E 0.5 PEG 400 1.0 Propylene glycol 1.5 Ethanol 15 Acetone 15 Propellant q.s. - More specific examples of compositions for use in an aerosol dispenser are set forth in Examples 3 through 5.
-
Ingredients Percent w/w Estradiol 1 PVP-K-30 6 PVP VA 4 Vitamin E 1 PEG 6000 2 Propylene glycol 3 P 12 58.1 P 11 24.9 -
Ingredients Percent w/w Estradiol 2 PVP K-30 6 PVP VA 4 Vitamin E 1 PEG 6000 2 Propylene glycol 3 P 12 24.9 P 11 57.1 -
Ingredients Percent w/w Alendronate sodium 1 PVP K-30 6 PVP VA 4 Vitamin E 0.5 Menthol 0.05 Dimethyl isosorbide 3.0 Acetone 10 Ethanol 10 Tetrafluoroethane (P134) 25.45 Dichlorodifluoromethane 40 (P12) - To prepare a composition according to the present invention suitable for use in a pump dispenser, the general method set forth above for an aerosol dispenser can be used, except that it is not necessary to charge the pump dispenser with liquefied propellant to provide a pressurized atmosphere. The mixture itself may contain propellant which is liquid at room temperature as part of the vehicle.
- Examples 6 through 9 represent partly generalized formulas which can be used with any suitable medicament to prepare compositions according to the present invention for use in a pump dispenser.
-
Ingredients Percent w/w Active ingredient 0.5-10.0 Plastoid B 5.6 Eudragit E 100 0.6 Propylene glycol 4.0 Sodium lauryl sulfate 3.0 Acetone 20 Isopropyl alcohol q.s. Vitamin E 0.2 Transcutol 2.0 -
Ingredients Percent w/w Active ingredient 25 Povidone 6 Povidone VA-64 4 Vitamin-E 1.0 Propylene glycol 3 Ethanol 27 Acetone q.s. Methylene chloride 27 -
Ingredients Percent w/w Active ingredient 15 PVP K 30 6 PVP VA 4 Vitamin-E TPGS 0.5 Dimethyl isosorbide 5 Ethanol 20 Trichloromonofluoromethane q.s. (P11) -
Ingredients Percent w/w Active ingredient 0.5-10 PVP VA 10 Vitamin E 0.5 Propylene glycol 3 Ethanol 25 Trichloromonofluoromethane q.s. (P11) - More specific examples of compositions which can be used in a pump dispenser are set forth in Examples 10 through 12.
-
Ingredients Percent w/w Estradiol 2 PVP K-30 6 PVP VA 4 Vitamin E 1 PEG 6000 2 Propylene glycol 3 Acetone 27 Methylene chloride 27 Ethanol 28 Dichlorodifluoromethane 40 (P12) -
Ingredients Percent w/w Estradiol 1 PVP K-30 6 PVP VA 4 Vitamin E 1 PEG 6000 2 Polyethylene glycol 3 Acetone 27 Methylene chloride 28 Ethanol 28 -
Ingredients Percent w/w Estradiol 1 PVP K-30 6 PVP VA 4 Vitamin E 1 Menthol 0.05 Dimethyl Isosorbide 5 Acetone 27.48 Ethanol 27.48 P11 27.48 - The following further explanation is given of the above examples. Eudragit E 100 is a self-adhesive, hydrophilic matrix system. It also acts as a solubilizer for the drug Estradiol. Plastoid B is a film-former. When used together, Eudragit E 100 and Plastoid B give better peelability and water washability than when either is used alone. Acetone is a volatile, quick-drying, non-occlusive vehicle which helps to dispense the contents of the spray over a large surface area. Propylene glycol acts as a humectant to prevent the excessive drying of the application site after application of the medicament. It also acts as a plasticizer for the film formed after application. Propylene glycol additionally acts as a solubilizer for the drug and a permeation enhancer. Sodium lauryl sulfate acts as a solubilizer for the drug
- Propellant is necessary for developing proper pressure within an aerosol container and for expulsion of the composition when the valve is open. It is also responsible, together with the valve, for dispensing the product as a fine spray. The preferred propellants are very stable compounds and relatively non-toxic, inert and non-flammable.
- The compositions in the above examples were discharged from the dispenser as a fine, soft dispersed spray which could be easily controlled to produce a stable thin film of even thickness on a target surface, for example, a laboratory cover glass. The films have been observed to last for at least 24 hours. The concentrations of the film-formers in the composition can be varied as required to obtain a patch which can deliver the drug in a sustained manner for a period of up to 1 to 5 days. The film is easily removable from the application site by water in preparation for reapplication of the film or other treatment.
- The embodiments illustrated and discussed in this specification are intended only to teach those skilled in the art the best way known to the inventors to make and use the invention. Nothing in this specification should be considered as limiting the scope of the present invention. The above-described embodiments of the invention may be modified or varied, and elements added or omitted, without departing from the invention, as appreciated by those skilled in the art in light of the above teachings. It is therefore to be understood that, within the scope of the claims and their equivalents, the invention may be practiced otherwise than as specifically described.
Claims (64)
1. A sprayable composition for topical application, comprising:
from about 0.0001% to about 30% of at least one medicament for systemic or topical availability,
at least one film former,
at least one vehicle; and at least one component selected from the group
at least one permeation enhancer:
at least one solubilizer:
at least one plasticizer; and
at least one water soluble additive
the composition forming a stable, breathable film upon application to a surface.
2. The composition according to claim 1 , comprising from about 0.0001% to about 10% of the at least one medicament.
3. The composition according to claim 1 , comprising from about 0.0001% to about 5% of the at least one medicament.
4. The composition according to claim 1 , wherein the film former comprises from about 0.0001% to about 10% of the composition.
5. (Canceled)
6. The composition according to claim 1 , comprising at least one permeation enhancer in an amount of from about 0.0001% to about 8% of the composition.
7. (Canceled)
8. The composition according to claim 1 , comprising at least one solubilizer in an amount of from about 0.0001% to about 10% of the composition.
9. (Canceled)
10. The composition according to claim 1 , comprising at least one plasticizer in an amount of from about 0.0001% to about 10% of the composition.
11. The composition according to claim 1 , the composition comprising at least one water soluble additive in an amount of from about 0.0001% to about 7%.
12. The composition according to claim 1 , wherein the at least one medicament is locally or transdermally available.
13. (Canceled)
14. The composition according to claim 1 , wherein the composition comprises at least one medicament which is released from the composition immediately upon application to a biological surface.
15. The composition according to claim 1 , wherein the composition comprises at least one medicament which is released from the composition over an extended period of time after application to a biological surface.
16. (Canceled)
17. The composition according to claim 1 , wherein the at least one medicament is selected from the group consisting of anti-emetics, anti-anginals, anti-inflammatory agents, steroids, steroid hormones, bronchodilators, drugs used to treat osteoporosis, drugs used to treat incontinence, antidepressants/anxiolytics, antimigraine agents, agents used in smoking cessation therapy, antidiarrheals, antiulcerants, anticholinerginics, anticonvulsants, drugs for mood disorders/obsessive compulsive disorder, ACE inhibitors, calcium channel blockers, antihypertensives/diuretics, antiobesity drugs, hormonal peptides and analogues, drugs for benign prostatic hyperplasia/urinary retention and erectile dysfunctions, antiparkinson agents such as dopamine agonists and MAO inhibitors, drugs for sleep disorders and antidiabetic agents.
18. The composition according to claim 1 , wherein the at least one medicament is selected from the group consisting of scopolamine, nitroglycerine, clonidine isosorbide dinitrate, propanolol hydrochloride, timolol maleate, clonazepam, verapamil, diclofenac sodium, naproxen sodium, ibuprofen, ketoprofen, indomethacin, piroxicam, ketorolac, tromethamine, nimesulide, hydrocortisone and esters thereof, dexamethasone, fluocinolone acetonide and betamethasone and salts thereof, estradiol and norethisterone or their pharmaceutically acceptable salts and combinations thereof, testosterone, progesterone, salbutamol and salts thereof, bambuterol, salmeterol xinafoate, fluticasone propionate, mometasone furoate, budesonide, beclomethasone dipropionate, sodium cromoglycate or isoprenaline sulphate, alendronic acid, pamidronic acid, etidronic acid or salts thereof, vasopressin, oxybutynin, imipramine, mitrazapine, desipramine, naratriptan, zolmitriptan, sumatriptan, nicotine, loperamide, misoprostol, hyoscyamine, atropine, trihexyphenidyl, lorazepam, diazepam, tiagabine, fluoxetine, paroxetine, lisinopril, trandolapril, captopril, amlodipine, felodipine, prazosin, amiloride, methamphetamine, sibutramine hydrochloride, nafarelin, leuprolide acetate, insulin, growth hormone and analogues thereof, doxazosin, tamsulosin, terazosin, finasteride, alprostadil, sildenafil citrate, bromocriptine, cabergoline, selegiline, melatonin, glimepiride, rosiglitazone, glyburide, glipizide and combinations thereof.
19. The composition according to claim 1 , wherein the at least one medicament is present as a single enantiomer.
20. The composition according to claim 6 , wherein the at least one permeation enhancer is selected from the group consisting of lipophilic solvents, surfactants, oleic acid, octyl dimethyl benzoic acid, menthol, mixed esters of capric and caprylic acid, polyhydric alcohols, dimethyl sulfoxide, dimethyl formamide, isopropyl myristate, Tween, sodium lauryl sulfate, propylene glycol, transcutol and combinations thereof.
21. (Canceled)
22. The composition according to claim 1 , wherein the at least one vehicle comprises water, at least one non-aqueous solvent, or at least one propellant.
23. The composition according to claim 22 , wherein the at least one non-aqueous solvent is selected from the group consisting of acetone, isopropyl alcohol, methylene chloride, methyl ethyl ketone, absolute alcohol, ethyl acetate trichloromonofluoroethane (P11) and methylene dimethyl ether.
24. (Canceled)
25. The composition according to claim 22 , wherein the at least one propellant comprises from about 10% to about 90% of the composition.
26. The composition according to claim 22 , wherein the at least one propellant is selected from the group consisting of a hydrocarbon, a hydrofluorocarbon, hydrochlorofluorocarbon, a compressed gas propane, butane, isobutane, dimethylether, dichlorodifluoromethane (P12), trichloromonofluoromethane (P11) dichlorofluoroethane, monochlorodifluoromethane (P22), dichlorotetrafluoroethane (P114), difluoroethane (P152A). tetrafluoroethane (P134A), heptafluoropropane (P227B), nitrogen and carbon dioxide.
27. (Canceled)
28. The composition according to claim 1 , wherein the at least one vehicle comprises from about 1% to about 20% (w/w) of at least one humectant.
29. The composition according to claim 28 , wherein the at least one humectant is selected from the group consisting of polyhydric alcohols polyvinyl pyrrolidone, propylene glycol, butylene glycol, a polyethylene glycol, glycerol and sorbitol.
30. (Canceled)
31. The composition according to claim 1 , wherein the at least one film-former is selected from the group consisting of acrylic polymers or copolymers, polyvinyl acetate, cellulose acetate, polyvinyl alcohol, povidone, copolypovidone povidone vinyl acetate, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl cellulose and ethyl cellulose.
32. The composition according to claim 31 , wherein the acrylic polymer or copolymer is selected from the group consisting of non-ionic copolymers of methyl methacrylate and butyl methacrylate, copolymers of dimethylamine ethyl methacrylate and a neutral methacrylic acid ester, ammonio methacrylate copolymer type B, ammonio methacrylate copolymer type A, methacrylic acid copolymer type A and methacrylic acid copolymer type B.
33. The composition according claim 8 , wherein the at least one solubilizer is selected from the group consisting of copolymers of dimethylamine ethyl methacrylate and a neutral methacrylic acid ester, a surfactant, a polyhydric alcohol, vitamin E, vitamin E TPGS (tocopheryl polyethylene 1000 succinate), labrasol, propylene carbonate, sodium laurel sulphate, Tweens, spans, propylene glycol polyethylene glycol and combinations thereof.
34. (Canceled)
35. The composition according to claim 10 , wherein the at least one plasticizer is selected from the group consisting of triethyl citrate, dimethyl isosorbide, acetyltributyl citrate, castor oil, propylene glycol, polyethylene glycol, and combinations thereof.
36. The composition according to claim 11 , wherein the at least one water soluble additive is selected from the group consisting of propylene glycol, sodium lauryl sulfate, one or more polaxomers, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, cetomacrogol, polyethylene glycol, diethylene glycol, monoethyl ether EP (transcutol), and combinations thereof.
37. The composition according to claim 1 , comprising:
from about 0.0001% to about 30% of at least one medicament for topical or systemic availability,
at least one film-former,
at least one solubilizer,
at least one permeation enhancer,
at least one plasticizer, and
at least one vehicle
said composition forming a stable, breathable film upon application to a surface.
38. The composition according to claim 37 , wherein the at least one medicament comprises from about 0.0001% to about 10% of the composition.
39. The composition according to claim 37 , wherein the at least one medicament comprises from about 0.0001% to about 5% of the composition.
40. The composition according to claim 37 , wherein the at least one film former comprises from about 0.0001% to about 10% of the composition, the at least one solubilizer comprises from about 0.0001% to about 10% of the composition, the at least one permeation enhancer comprises from about 0.0001% to about 8% of the composition, and the at least one plasticizer comprises from about 0.0001% to about 10% of the compositi.
41-43. (Canceled)
44. The composition according to claim 37 , further comprising from about 0.0001% to about 7% of at least one water soluble additive.
45. The composition according to claim 37 , wherein the film-former is a non-ionic copolymer of methyl methacrylate and butyl methacrylate and the solubilizer is a copolymer of dimethylamine ethyl methacrylate and a neutral methacrylic acid ester.
46. A stable, breathable film formed on the skin by topically applying a composition to an intended application site, said composition comprising
from about 0.001% to about 30% of at least one medicament for topical or systemic availability,
at least one film-former;
at least one vehicle; and at least one component selected from the group
at least one permeation enhancer;
at least one solubilizer;
at least one plasticizer, and
at least one water soluble additive.
47. The film according to claim 46 , wherein the composition comprises up to about 10% of the at least one medicament.
48. The film according to claim 46 , wherein the composition comprises up to about 5% of the at least one medicament.
49-51. (Canceled)
52. The film according to claim 46 , wherein the film is formed over a fixed surface area.
53. The film according to claim 52 , wherein the fixed surface area is less than about 50cm2.
54. The film according to claim 52 , wherein the fixed surface area is from about 10 cm2 to about 25 cm2.
55. The film according to claim 46 , wherein the at least one medicament is locally or transdermally available.
56. A stable, breathable film formed on the skin by topically applying a composition according to claim 37 .
57. A method of using at least one medicament, comprising the steps of:
providing a composition for topical application, and
dispensing a metered dose of said composition onto an intended application site on the skin;
wherein the composition comprises from about 0.0001% to about 30% of at least one medicament for systemic or topical availability,
at least one film former,
at least one vehicle; and at least one component selected from the group
at least one permeation enhancer;
at least one solubilizer;
at least one plasticizer; and
at least one water soluble additive.
58. The method according to claim 57 , wherein the composition comprises up to about 10% of the at least one medicament.
59. The method according to claim 57 , wherein the composition comprises up to about 5% of the at least one medicament.
60. The method according to claim 57 , wherein the at least one film former comprises from about 0.0001% to about 10% of the composition.
61-66. (Canceled)
67. The method according to claim 57 , wherein the metered dose is dispensed over a fixed surface area.
68. The method according to claim 67 , wherein the fixed surface area is not more than about 50 cm2.
69. The method according to claim 68 , wherein the fixed surface area is from about 10 cm2 to about 25 cm2.
70. The method according to claim 57 , wherein said dispensing comprises spraying.
71. The method according to claim 57 , wherein the composition forms a stable, breathable film after dispensing on the application site.
72. The method of claim 70 , wherein said dispensing is conducted by an apparatus selected from the group consisting of a pump dispenser and an aerosol dispenser.
73. (Canceled)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
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US10/686,517 US20040213744A1 (en) | 1999-05-20 | 2003-10-16 | Topical spray compositions |
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US09/503,843 US6962691B1 (en) | 1999-05-20 | 2000-02-15 | Topical spray compositions |
US10/686,517 US20040213744A1 (en) | 1999-05-20 | 2003-10-16 | Topical spray compositions |
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US09/503,843 Continuation US6962691B1 (en) | 1999-05-20 | 2000-02-15 | Topical spray compositions |
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