MXPA96003667A - Composed transdermal supply device adhesive containing dr - Google Patents
Composed transdermal supply device adhesive containing drInfo
- Publication number
- MXPA96003667A MXPA96003667A MXPA/A/1996/003667A MX9603667A MXPA96003667A MX PA96003667 A MXPA96003667 A MX PA96003667A MX 9603667 A MX9603667 A MX 9603667A MX PA96003667 A MXPA96003667 A MX PA96003667A
- Authority
- MX
- Mexico
- Prior art keywords
- drug
- adhesive
- adhesive layer
- layer
- laminate
- Prior art date
Links
- 239000000853 adhesive Substances 0.000 title claims abstract description 265
- 230000001070 adhesive Effects 0.000 title claims abstract description 265
- 239000003814 drug Substances 0.000 claims abstract description 194
- 229940079593 drugs Drugs 0.000 claims abstract description 194
- 239000000463 material Substances 0.000 claims abstract description 50
- 210000003491 Skin Anatomy 0.000 claims abstract description 48
- 239000002131 composite material Substances 0.000 claims abstract description 34
- 238000004519 manufacturing process Methods 0.000 claims abstract description 26
- 210000004877 mucosa Anatomy 0.000 claims abstract description 25
- 229940089114 Drug Delivery Device Drugs 0.000 claims abstract 6
- SNICXCGAKADSCV-JTQLQIEISA-N Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 claims description 95
- 229960002715 Nicotine Drugs 0.000 claims description 91
- 229930015196 nicotine Natural products 0.000 claims description 91
- 150000001875 compounds Chemical class 0.000 claims description 39
- 239000000203 mixture Substances 0.000 claims description 33
- 238000000034 method Methods 0.000 claims description 25
- -1 polysiloxanes Polymers 0.000 claims description 18
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 15
- 238000001125 extrusion Methods 0.000 claims description 15
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 15
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 14
- 239000003795 chemical substances by application Substances 0.000 claims description 13
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N Oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 12
- 230000002708 enhancing Effects 0.000 claims description 12
- 229920001577 copolymer Polymers 0.000 claims description 11
- 238000009792 diffusion process Methods 0.000 claims description 11
- 238000009472 formulation Methods 0.000 claims description 11
- 238000003475 lamination Methods 0.000 claims description 11
- 230000035699 permeability Effects 0.000 claims description 11
- 238000007792 addition Methods 0.000 claims description 10
- 239000003963 antioxidant agent Substances 0.000 claims description 9
- 235000006708 antioxidants Nutrition 0.000 claims description 9
- 239000003623 enhancer Substances 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 8
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 8
- 229920000728 polyester Polymers 0.000 claims description 8
- 150000002009 diols Chemical class 0.000 claims description 7
- 230000035515 penetration Effects 0.000 claims description 7
- 239000005642 Oleic acid Substances 0.000 claims description 6
- BAECOWNUKCLBPZ-HIUWNOOHSA-N Triolein Natural products O([C@H](OCC(=O)CCCCCCC/C=C\CCCCCCCC)COC(=O)CCCCCCC/C=C\CCCCCCCC)C(=O)CCCCCCC/C=C\CCCCCCCC BAECOWNUKCLBPZ-HIUWNOOHSA-N 0.000 claims description 6
- 230000003078 antioxidant Effects 0.000 claims description 6
- 238000010030 laminating Methods 0.000 claims description 6
- 229920001296 polysiloxane Polymers 0.000 claims description 6
- 229920002635 polyurethane Polymers 0.000 claims description 6
- 239000004814 polyurethane Substances 0.000 claims description 6
- RZRNAYUHWVFMIP-KTKRTIGZSA-N 1-oleoylglycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(O)CO RZRNAYUHWVFMIP-KTKRTIGZSA-N 0.000 claims description 5
- HNJBEVLQSNELDL-UHFFFAOYSA-N 2-Pyrrolidone Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims description 5
- ARIWANIATODDMH-UHFFFAOYSA-N Monolaurin Chemical compound CCCCCCCCCCCC(=O)OCC(O)CO ARIWANIATODDMH-UHFFFAOYSA-N 0.000 claims description 5
- ALSTYHKOOCGGFT-KTKRTIGZSA-N Oleyl alcohol Chemical compound CCCCCCCC\C=C/CCCCCCCCO ALSTYHKOOCGGFT-KTKRTIGZSA-N 0.000 claims description 5
- XAPRFLSJBSXESP-UHFFFAOYSA-N Oxycinchophen Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=C(O)C=1C1=CC=CC=C1 XAPRFLSJBSXESP-UHFFFAOYSA-N 0.000 claims description 5
- 229920002614 Polyether block amide Polymers 0.000 claims description 5
- JNYAEWCLZODPBN-CTQIIAAMSA-N Sorbitan Chemical class OCC(O)C1OCC(O)[C@@H]1O JNYAEWCLZODPBN-CTQIIAAMSA-N 0.000 claims description 5
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 5
- 229940071676 hydroxypropylcellulose Drugs 0.000 claims description 5
- 239000002085 irritant Substances 0.000 claims description 5
- UQDUPQYQJKYHQI-UHFFFAOYSA-N methyl laurate Chemical compound CCCCCCCCCCCC(=O)OC UQDUPQYQJKYHQI-UHFFFAOYSA-N 0.000 claims description 5
- 229940055577 oleyl alcohol Drugs 0.000 claims description 5
- 229920000058 polyacrylate Polymers 0.000 claims description 5
- XTXRWKRVRITETP-UHFFFAOYSA-N vinyl acetate Chemical class CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 claims description 5
- AFSHUZFNMVJNKX-CLFAGFIQSA-N 1,2-dioleoylglycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(CO)OC(=O)CCCCCCC\C=C/CCCCCCCC AFSHUZFNMVJNKX-CLFAGFIQSA-N 0.000 claims description 4
- WDQFELCEOPFLCZ-UHFFFAOYSA-N 1-(2-hydroxyethyl)pyrrolidin-2-one Chemical compound OCCN1CCCC1=O WDQFELCEOPFLCZ-UHFFFAOYSA-N 0.000 claims description 4
- YQEMORVAKMFKLG-UHFFFAOYSA-N 2-stearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 claims description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N DMA Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 4
- 229940031574 HYDROXYMETHYL CELLULOSE Drugs 0.000 claims description 4
- 229960002969 Oleic Acid Drugs 0.000 claims description 4
- 229940026235 PROPYLENE GLYCOL MONOLAURATE Drugs 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 4
- LLRANSBEYQZKFY-UHFFFAOYSA-N dodecanoic acid;propane-1,2-diol Chemical compound CC(O)CO.CCCCCCCCCCCC(O)=O LLRANSBEYQZKFY-UHFFFAOYSA-N 0.000 claims description 4
- 229960005150 glycerol Drugs 0.000 claims description 4
- 229920003063 hydroxymethyl cellulose Polymers 0.000 claims description 4
- 238000002844 melting Methods 0.000 claims description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N n-methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 4
- 229920001194 natural rubber Polymers 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 239000011780 sodium chloride Substances 0.000 claims description 4
- 230000002459 sustained Effects 0.000 claims description 4
- 229920003051 synthetic elastomer Polymers 0.000 claims description 4
- 239000005061 synthetic rubber Substances 0.000 claims description 4
- 239000002562 thickening agent Substances 0.000 claims description 4
- 229920000609 methyl cellulose Polymers 0.000 claims description 3
- 239000001923 methylcellulose Substances 0.000 claims description 3
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 claims description 3
- 239000005977 Ethylene Substances 0.000 claims description 2
- 238000005096 rolling process Methods 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims 6
- 239000003961 penetration enhancing agent Substances 0.000 claims 6
- AXISYYRBXTVTFY-UHFFFAOYSA-N Isopropyl myristate Chemical compound CCCCCCCCCCCCCC(=O)OC(C)C AXISYYRBXTVTFY-UHFFFAOYSA-N 0.000 claims 3
- 238000010924 continuous production Methods 0.000 claims 3
- 229940074928 isopropyl myristate Drugs 0.000 claims 3
- 229920003229 poly(methyl methacrylate) Polymers 0.000 claims 3
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2R,3R,4S,5R,6S)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2S,3R,4S,5R,6R)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2R,3R,4S,5R,6R)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 claims 2
- 229960002900 Methylcellulose Drugs 0.000 claims 2
- 239000002973 irritant agent Substances 0.000 claims 2
- 238000005063 solubilization Methods 0.000 claims 1
- 238000004078 waterproofing Methods 0.000 claims 1
- 239000000499 gel Substances 0.000 description 26
- 239000000543 intermediate Substances 0.000 description 23
- 239000007788 liquid Substances 0.000 description 15
- 229920000642 polymer Polymers 0.000 description 14
- 239000000126 substance Substances 0.000 description 14
- 239000011159 matrix material Substances 0.000 description 10
- 238000001035 drying Methods 0.000 description 9
- 238000000465 moulding Methods 0.000 description 9
- 210000004379 Membranes Anatomy 0.000 description 8
- 239000011248 coating agent Substances 0.000 description 8
- 238000000576 coating method Methods 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 239000012528 membrane Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 229940095259 Butylated Hydroxytoluene Drugs 0.000 description 7
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 7
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 7
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 7
- 239000003349 gelling agent Substances 0.000 description 7
- PPBRXRYQALVLMV-UHFFFAOYSA-N styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 6
- 201000010099 disease Diseases 0.000 description 5
- 230000001965 increased Effects 0.000 description 5
- 230000000391 smoking Effects 0.000 description 5
- 239000004698 Polyethylene (PE) Substances 0.000 description 4
- 239000002250 absorbent Substances 0.000 description 4
- 230000002745 absorbent Effects 0.000 description 4
- 229910002056 binary alloy Inorganic materials 0.000 description 4
- 230000015556 catabolic process Effects 0.000 description 4
- 230000004059 degradation Effects 0.000 description 4
- 238000006731 degradation reaction Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000011888 foil Substances 0.000 description 4
- 238000011068 load Methods 0.000 description 4
- 230000000144 pharmacologic effect Effects 0.000 description 4
- 229920000573 polyethylene Polymers 0.000 description 4
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 4
- 230000002633 protecting Effects 0.000 description 4
- 238000003860 storage Methods 0.000 description 4
- 210000000434 stratum corneum Anatomy 0.000 description 4
- 229940023808 Albuterol Drugs 0.000 description 3
- 239000004821 Contact adhesive Substances 0.000 description 3
- 229920002367 Polyisobutene Polymers 0.000 description 3
- 229920001328 Polyvinylidene chloride Polymers 0.000 description 3
- NDAUXUAQIAJITI-UHFFFAOYSA-N Salbutamol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000003522 acrylic cement Substances 0.000 description 3
- 125000003342 alkenyl group Chemical group 0.000 description 3
- 230000000111 anti-oxidant Effects 0.000 description 3
- 235000019504 cigarettes Nutrition 0.000 description 3
- 238000005520 cutting process Methods 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- 235000011187 glycerol Nutrition 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 230000002335 preservative Effects 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 229960002052 salbutamol Drugs 0.000 description 3
- 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 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K 2qpq Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- 238000003855 Adhesive Lamination Methods 0.000 description 2
- 206010012335 Dependence Diseases 0.000 description 2
- 229960005309 Estradiol Drugs 0.000 description 2
- 229940015769 Nicotine Chewing Gum Drugs 0.000 description 2
- 206010040880 Skin irritation Diseases 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K [O-]P([O-])([O-])=O Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 230000000202 analgesic Effects 0.000 description 2
- 230000001139 anti-pruritic Effects 0.000 description 2
- 239000003908 antipruritic agent Substances 0.000 description 2
- 239000000560 biocompatible material Substances 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 229920001971 elastomer Polymers 0.000 description 2
- 239000004744 fabric Substances 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 238000005755 formation reaction Methods 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 230000000622 irritating Effects 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- RRHGJUQNOFWUDK-UHFFFAOYSA-N isoprene Chemical compound CC(=C)C=C RRHGJUQNOFWUDK-UHFFFAOYSA-N 0.000 description 2
- 230000000670 limiting Effects 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 235000019271 petrolatum Nutrition 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 2
- 239000005033 polyvinylidene chloride Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000002035 prolonged Effects 0.000 description 2
- 230000001681 protective Effects 0.000 description 2
- 230000001105 regulatory Effects 0.000 description 2
- 230000002787 reinforcement Effects 0.000 description 2
- 230000003014 reinforcing Effects 0.000 description 2
- 231100000475 skin irritation Toxicity 0.000 description 2
- 230000036556 skin irritation Effects 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 2
- 230000037317 transdermal delivery Effects 0.000 description 2
- SNIOPGDIGTZGOP-UHFFFAOYSA-N 1,2,3-propanetrioltrinitrate Chemical compound [O-][N+](=O)OCC(O[N+]([O-])=O)CO[N+]([O-])=O SNIOPGDIGTZGOP-UHFFFAOYSA-N 0.000 description 1
- AXTGDCSMTYGJND-UHFFFAOYSA-N 1-dodecylazepan-2-one Chemical compound CCCCCCCCCCCCN1CCCCCC1=O AXTGDCSMTYGJND-UHFFFAOYSA-N 0.000 description 1
- GJSURZIOUXUGAL-UHFFFAOYSA-N 2-((2,6-Dichlorophenyl)imino)imidazolidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 description 1
- 229930000680 A04AD01 - Scopolamine Natural products 0.000 description 1
- 229940035676 ANALGESICS Drugs 0.000 description 1
- 229940036592 ANTHELMINTICS Drugs 0.000 description 1
- 229940005513 ANTIDEPRESSANTS Drugs 0.000 description 1
- 229940116904 ANTIINFLAMMATORY THERAPEUTIC RADIOPHARMACEUTICALS Drugs 0.000 description 1
- 229940005529 ANTIPSYCHOTICS Drugs 0.000 description 1
- 206010000059 Abdominal discomfort Diseases 0.000 description 1
- 210000003165 Abomasum Anatomy 0.000 description 1
- 229940064005 Antibiotic throat preparations Drugs 0.000 description 1
- 229940083879 Antibiotics FOR TREATMENT OF HEMORRHOIDS AND ANAL FISSURES FOR TOPICAL USE Drugs 0.000 description 1
- 229940042052 Antibiotics for systemic use Drugs 0.000 description 1
- 229940042786 Antitubercular Antibiotics Drugs 0.000 description 1
- 230000035639 Blood Levels Effects 0.000 description 1
- 229940030609 CALCIUM CHANNEL BLOCKERS Drugs 0.000 description 1
- 229940037530 COUGH AND COLD PREPARATIONS Drugs 0.000 description 1
- 210000003169 Central Nervous System Anatomy 0.000 description 1
- 206010054938 Cerebral disease Diseases 0.000 description 1
- 229940112822 Chewing Gum Drugs 0.000 description 1
- 208000004981 Coronary Disease Diseases 0.000 description 1
- 229940064701 Corticosteroid nasal preparations for topical use Drugs 0.000 description 1
- 229960001334 Corticosteroids Drugs 0.000 description 1
- 229960001305 Cysteine Hydrochloride Drugs 0.000 description 1
- 229940030606 DIURETICS Drugs 0.000 description 1
- 206010061428 Decreased appetite Diseases 0.000 description 1
- 210000004207 Dermis Anatomy 0.000 description 1
- LQZZUXJYWNFBMV-UHFFFAOYSA-N Dodecanol Chemical compound CCCCCCCCCCCCO LQZZUXJYWNFBMV-UHFFFAOYSA-N 0.000 description 1
- 239000004819 Drying adhesive Substances 0.000 description 1
- 210000002615 Epidermis Anatomy 0.000 description 1
- 229940011871 Estrogens Drugs 0.000 description 1
- 229940093922 Gynecological Antibiotics Drugs 0.000 description 1
- 229940088597 Hormone Drugs 0.000 description 1
- STECJAGHUSJQJN-GAUPFVANSA-N Hyoscine Natural products C1([C@H](CO)C(=O)OC2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-GAUPFVANSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 229940035363 MUSCLE RELAXANTS Drugs 0.000 description 1
- TTWJBBZEZQICBI-UHFFFAOYSA-N Metoclopramide Chemical compound CCN(CC)CCNC(=O)C1=CC(Cl)=C(N)C=C1OC TTWJBBZEZQICBI-UHFFFAOYSA-N 0.000 description 1
- 210000004400 Mucous Membrane Anatomy 0.000 description 1
- 229940083876 Muscle relaxants FOR TREATMENT OF HEMORRHOIDS AND ANAL FISSURES FOR TOPICAL USE Drugs 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 229940014995 Nitroglycerin Drugs 0.000 description 1
- 239000000006 Nitroglycerin Substances 0.000 description 1
- 239000004677 Nylon Substances 0.000 description 1
- 229940074726 OPHTHALMOLOGIC ANTIINFLAMMATORY AGENTS Drugs 0.000 description 1
- 229940030490 PROGESTOGEN SEX HORMONES AND MODULATORS OF THE GENITAL SYSTEM Drugs 0.000 description 1
- 235000014676 Phragmites communis Nutrition 0.000 description 1
- 239000004952 Polyamide Substances 0.000 description 1
- 229920001896 Polybutyrate Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- 229920001451 Polypropylene glycol Polymers 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 229940095055 Progestogen systemic hormonal contraceptives Drugs 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 229940030484 SEX HORMONES AND MODULATORS OF THE GENITAL SYSTEM ESTROGENS Drugs 0.000 description 1
- STECJAGHUSJQJN-FWXGHANASA-N Scopolamine Chemical compound C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-FWXGHANASA-N 0.000 description 1
- CSMWJXBSXGUPGY-UHFFFAOYSA-L Sodium dithionate Chemical compound [Na+].[Na+].[O-]S(=O)(=O)S([O-])(=O)=O CSMWJXBSXGUPGY-UHFFFAOYSA-L 0.000 description 1
- 239000000150 Sympathomimetic Substances 0.000 description 1
- 229940064707 Sympathomimetics Drugs 0.000 description 1
- AOBORMOPSGHCAX-DGHZZKTQSA-N Tocofersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2O[C@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-DGHZZKTQSA-N 0.000 description 1
- 229940024982 Topical Antifungal Antibiotics Drugs 0.000 description 1
- 206010068760 Ulcers Diseases 0.000 description 1
- LRFVTYWOQMYALW-UHFFFAOYSA-N Xanthine Chemical class O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 1
- QIJRTFXNRTXDIP-JIZZDEOASA-N [(1R)-1-carboxy-2-sulfanylethyl]azanium;chloride;hydrate Chemical compound O.Cl.SC[C@H](N)C(O)=O QIJRTFXNRTXDIP-JIZZDEOASA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-M acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 229940053550 agents used for ADHD and nootropics psychostimulants Xanthine derivatives Drugs 0.000 description 1
- 238000005054 agglomeration Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229940087168 alpha Tocopherol Drugs 0.000 description 1
- 239000002160 alpha blocker Substances 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N alpha-Tocopherol Natural products OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminum Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 230000003444 anaesthetic Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000578 anorexic Effects 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 230000000507 anthelmentic Effects 0.000 description 1
- 239000000921 anthelmintic agent Substances 0.000 description 1
- 230000003288 anthiarrhythmic Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000001396 anti-anti-diuretic Effects 0.000 description 1
- 230000002456 anti-arthritic Effects 0.000 description 1
- 230000001078 anti-cholinergic Effects 0.000 description 1
- 230000001773 anti-convulsant Effects 0.000 description 1
- 230000001430 anti-depressive Effects 0.000 description 1
- 230000001142 anti-diarrhea Effects 0.000 description 1
- 230000002686 anti-diuretic Effects 0.000 description 1
- 230000000118 anti-eoplastic Effects 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 230000003276 anti-hypertensive Effects 0.000 description 1
- 230000002924 anti-infective Effects 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000002460 anti-migraine Effects 0.000 description 1
- 230000000561 anti-psychotic Effects 0.000 description 1
- 230000001754 anti-pyretic Effects 0.000 description 1
- 230000002921 anti-spasmodic Effects 0.000 description 1
- 239000003416 antiarrhythmic agent Substances 0.000 description 1
- 239000000924 antiasthmatic agent Substances 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 239000003793 antidiarrheal agent Substances 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 239000000164 antipsychotic agent Substances 0.000 description 1
- 239000002221 antipyretic Substances 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 230000003115 biocidal Effects 0.000 description 1
- 230000002051 biphasic Effects 0.000 description 1
- 229920001400 block copolymer Polymers 0.000 description 1
- KAKZBPTYRLMSJV-UHFFFAOYSA-N butadiene Chemical compound C=CC=C KAKZBPTYRLMSJV-UHFFFAOYSA-N 0.000 description 1
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000000271 cardiovascular Effects 0.000 description 1
- 235000015218 chewing gum Nutrition 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 229960002896 clonidine Drugs 0.000 description 1
- 201000008739 coronary artery disease Diseases 0.000 description 1
- 230000000875 corresponding Effects 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 230000001186 cumulative Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- 239000000850 decongestant Substances 0.000 description 1
- 238000000151 deposition Methods 0.000 description 1
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Substances OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 1
- 201000009910 diseases by infectious agent Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 201000006549 dyspepsia Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N edta Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 239000000806 elastomer Substances 0.000 description 1
- 229940046080 endocrine therapy drugs Estrogens Drugs 0.000 description 1
- 229940046079 endocrine therapy drugs Progestogens Drugs 0.000 description 1
- 238000011067 equilibration Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229920001038 ethylene copolymer Polymers 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000007765 extrusion coating Methods 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 230000004907 flux Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N fumaric acid Chemical compound OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 150000002314 glycerols Chemical class 0.000 description 1
- 229960003711 glyceryl trinitrate Drugs 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 239000003326 hypnotic agent Substances 0.000 description 1
- 230000001506 immunosuppresive Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 229940079866 intestinal antibiotics Drugs 0.000 description 1
- 238000005304 joining Methods 0.000 description 1
- 239000012035 limiting reagent Substances 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 229940083747 low-ceiling diuretics Xanthine derivatives Drugs 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 229960004503 metoclopramide Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000006011 modification reaction Methods 0.000 description 1
- 239000003158 myorelaxant agent Substances 0.000 description 1
- IMNFDUFMRHMDMM-UHFFFAOYSA-N n-heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 229920001778 nylon Polymers 0.000 description 1
- 229940005935 ophthalmologic Antibiotics Drugs 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 230000002445 parasympatholytic Effects 0.000 description 1
- 230000037368 penetrate the skin Effects 0.000 description 1
- 230000037025 penetration rate Effects 0.000 description 1
- 230000002093 peripheral Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 239000011528 polyamide (building material) Substances 0.000 description 1
- 229920002857 polybutadiene Polymers 0.000 description 1
- 229920000515 polycarbonate Polymers 0.000 description 1
- 239000004417 polycarbonate Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000139 polyethylene terephthalate Polymers 0.000 description 1
- 239000005020 polyethylene terephthalate Substances 0.000 description 1
- 229920001195 polyisoprene Polymers 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 239000004810 polytetrafluoroethylene Substances 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 229920000915 polyvinyl chloride Polymers 0.000 description 1
- 239000004800 polyvinyl chloride Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000003450 potassium channel blocker Substances 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 239000000583 progesterone congener Substances 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propanol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003368 psychostimulant agent Substances 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 239000005060 rubber Substances 0.000 description 1
- 229960002646 scopolamine Drugs 0.000 description 1
- 230000001624 sedative Effects 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 230000037307 sensitive skin Effects 0.000 description 1
- 230000014860 sensory perception of taste Effects 0.000 description 1
- 231100000486 side effect Toxicity 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 239000000021 stimulant Substances 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- 230000001975 sympathomimetic Effects 0.000 description 1
- 230000001839 systemic circulation Effects 0.000 description 1
- 230000035917 taste Effects 0.000 description 1
- 235000019640 taste Nutrition 0.000 description 1
- KKEYFWRCBNTPAC-UHFFFAOYSA-L terephthalate(2-) Chemical compound [O-]C(=O)C1=CC=C(C([O-])=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-L 0.000 description 1
- 210000001519 tissues Anatomy 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- 230000000699 topical Effects 0.000 description 1
- 229940083878 topical for treatment of hemorrhoids and anal fissures Corticosteroids Drugs 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000002936 tranquilizing Effects 0.000 description 1
- 239000003204 tranquilizing agent Substances 0.000 description 1
- 150000004072 triols Chemical class 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 239000005526 vasoconstrictor agent Substances 0.000 description 1
- 230000000261 vasodilator Effects 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 231100000925 very toxic Toxicity 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
Abstract
The present invention relates to a method for manufacturing a transdermal or transmucosal drug delivery device, which includes a drug-containing adhesive composite layer, consisting essentially of first and second adhesive layers permeable to the drug, which contains a drug in gel form, said composite layer has a distant bottom material impermeable to the drug laminated on the distant surface of the composite layer and a close release film, which is essentially impermeable to the drug and which is adapted to be removed by administration of a drug to the skin or mucosa laminated to the proximal surface of the composite layer, the method comprises the steps of: (a) providing a first adhesive laminate comprising the first adhesive layer, having laminated on a surface thereof, the background material distant and having the exposed surface of the first adhesive layer exposed, (b) providing a second adhesive laminate which it comprises the second adhesive layer, which has laminated on one surface thereof, the next release film and having the opposite surface of the second adhesive layer exposed, (c) extruding the drug, in gel form, towards at least one exposed surface of the first or second adhesive laminate, and (d) laminate together the exposed surfaces of the first adhesive laminate and the second adhesive laminate, at least one of which contains the extruded gelled drug, in such a way that the first and second second adhesive layers and the gelled drug combine to form the adhesive composite layer containing drug having the distant bottom material covering one surface thereof and the next release film covering the opposite surface of the same.
Description
"ADHESIVE COMPOSED TRANSDERMAL SUPPLY DEVICE CONTAINING DRUG"
BACKGROUND OF THE INVENTION
This invention relates generally to transdermal and transmucosal drug delivery devices (TDD). More particularly, the invention relates to TDD devices for delivering heat-sensitive or volatile drugs wherein the drug is extruded as a gel to an adhesive layer after which the surface of the adhesive layer to which the gel has been extruded. it is laminated with a second adhesive layer to form a composite drug-containing adhesive device. Chemical reinforcers to facilitate the transport of the drug through the skin or mucosa or other additives can also be mixed with the drug or in the composite device. In this manner, the invention encompasses a method for manufacturing TDD devices using an extrusion step for incorporating a gelled drug into a dried adhesive layer with drug delivery devices manufactured using the method. These methods and devices are particularly useful for delivering nicotine in the body.
Cigarette smoking is a major risk factor in coronary heart disease and is responsible for approximately 30 percent of cancer deaths. However, it is difficult to stop smoking any therapy to stop smoking has to deal with both pharmacological and psychological dependency on cigarettes. Modest success has been achieved by separating treatment from these two factors, such as satisfying the vehemently pharmacological desire with nicotine pills or chewing gum, while psychological addiction is treated independently. One of the most satisfying approaches depends on the nicotine chewing gum, which achieves the direct supply of nicotine in the systemic circulation through oral absorption. However, nicotine chewing gum tastes unpleasant and can lead to ulcers and heartburn in the mouth, and destroys dental appliances. In addition, complacency in the patient is crucial for effectiveness. Other problems with nicotine administered orally include stomach upsets, nausea, rapid degradation of nicotine and regular and unpredictable blood levels. Another approach is acquiring increased favor to treat pharmacological dependence on smoking cigarettes is the transdermal nicotine supply. The skin, in general, is a very effective barrier for the passage of materials from the environment to the body. However, nicotine is very volatile, highly soluble in lipid and easily penetrates the skin. For example, a comparison of the average penetration rates of other agents transdermally administered through the skin shows that nitroglycerin has a skin flux of 10-25 micrograms per square centimeter • hour, scopolamine of 2 to 8 micrograms per centimeter square • hour, estradiol from 0.01 to 0.03 microgram per square centimeters' hour, clonidine, 0.5 microgram per square centimeter-hour and nicotine from 100 to 300 micrograms per square centimeter-hour. However, nicotine is also very irritating to the skin and is very toxic. Therefore, the development of acceptable TDD devices to deliver nicotine has required finding ways to minimize irritation and safety issues while delivering effective doses of the substance. A number of TDD devices have been described for delivering nicotine. Japanese Application Number 61-251619 discloses an uncontrolled release device that retains low amounts of the substance and covers a relatively large area of the skin (70 square centimeters). U.S. Patent No. 4,597,961 issued to Etscorn discloses a device in which a microporous membrane minimally controls the release of nicotine to the skin in such a way that it is effective for only 45 minutes. The North American Patents Numbers 4, 920,989 and 5,016,652, issued to Rose et al., Disclose a nicotine patch that is preferably used with a nicotine aerosol spray that is delivered to the patient's mouth. U.S. Patent No. 4,943,435 issued to Baker et al. Discloses a transdermal patch for delivering nicotine for periods of 12 to 24 hours that includes a nicotine deposit and a regimen control polymer matrix to regulate the diffusion of nicotine to through the skin. U.S. Patent No. 4,908,213 issued to Govil et al. Discloses a transdermal nicotine patch containing an antipruritic to counteract the serious itching that may occur with the transdermal administration of nicotine. U.S. Patent No. 4,877,618 issued to Reed discloses a transdermal nicotine patch containing a stack of alternative layers of adhesive and interlaminar to provide a relatively constant rate of diffusion through the skin over a prolonged period of time.
The methods for manufacturing TDD devices have not received much attention in the patent literature. U.S. Patent No. 4,943,435, issued to Baker et al., Discloses a method for making a nicotine patch wherein the nicotine is preferably dissolved in an inert polymer matrix that controls the nicotine release rate. The percentage by weight of nicotine can be varied according to the desired loading in the monolithic matrix layer, however, to more than about 50 percent by weight of nicotine, the polymer stops solidifying properly after being molded, remaining in gel form. or fluid. Therefore, this method for making nicotine patches is limited to polymers and nicotine fillers which, when mixed, polymerize properly. Another problem with drug delivery devices containing polymers and volatile drugs is that, even when polymerization is achieved in the presence of the drug, the polymer-drug combination must be left to dry. This is a problem for volatile drugs, such as nicotine, since the concentration of the volatile drug will decrease during drying, especially if the polymer is heated in an oven to accelerate drying. Therefore, it would be advantageous to avoid manufacturing methods that require heating or drying after the addition of a volatile drug to the polymer. Baker also discloses that many of the common materials from which TDD devices are manufactured, such as reinforcements, adhesives, membranes, matrices and release liners, are dissolved or degraded by nicotine. For example, Baker reveals that adhesives become fibrous, lose their payback or are loaded so intensely with nicotine that they provide a huge burst of nicotine when applied to the skin. According to Baker, typical kinds of adhesives based on polyisobutylene, acrylate or silicone behave in this way when exposed to nicotine for as little as one week. Baker further discloses that polymers that swell significantly, disintegrate or completely dissolve in the presence of nicotine, include many kinds of polyvinyl chloride, polycarbonate, polystyrene, polyethylene terephthalate, polybutyrate, polyurethane, ethylene copolymers and vinyl acetate (except those with low percentages of vinyl acetate), and polyvinylidene chloride. U.S. Patent No. 4,915,950, issued to Miranda et al., Discloses a method for manufacturing TDD devices that involves laminating an adhesive anchor layer to a bottom layer impermeable to the drug. Similarly, a pressure sensitive contact adhesive is laminated in a release forum. Then, a layer of an absorbent source is deposited towards and preferably the contact layer or the anchor adhesive. Then, a drug in liquid form is stamped onto the exposed face of the absorbent source layer. Finally, the laminate of the anchor / bottom layer adhesive is laminated to the source / contact adhesive / release liner to form the finished device. The stamping step involves depositing the liquid drug into the layer of the absorbent source in an essentially uniform manner by any of a number of techniques. The use of a drug in liquid form is a considerable problem because the drug must moisten the surface of the source layer so that pressing the liquid towards the periphery of the device during lamination is considerably prevented. After the deposition, the drug diffuses into one or both of the adjacent adhesive layers. Therefore, the fabric material making up the source layer and its surface properties should be carefully selected so that the embedment towards the fabric is carefully controlled. The regime to which the liquid drug is printed to the source layer and the subsequent lamination in the adhesive laminate, therefore, must also be carefully controlled, which is difficult to do. U.S. Patent No. 5,110,599, issued to Anhuser also discloses a method for producing transdermal patches through a stamping process.OBJECTS AND COMPENDIUM OF THE INVENTION
It is an object of the present invention to provide a method for manufacturing laminated TDD devices that is compatible with volatile or heat sensitive drugs, boosters or other components that can not be subjected to drying or heating, such as occurs in an oven. Another object of the invention is to provide a method for manufacturing laminated TDD devices where absorption or embedding of a liquid drug formulation into an absorbent layer is not required. A further object of the invention is to provide a method for manufacturing laminated TDD devices that allows selection and optimization of drug delivery profiles.
These and other objects can be achieved by a method for manufacturing a TDD device comprising the steps of: (a) providing a first adhesive laminate comprising a first adhesive layer permeable to the drug having a laminate on a surface thereof; distant bottom layer material and having the opposite surface exposed; (b) providing a second adhesive laminate comprising a second adhesive layer having a laminate on a surface thereof, a release liner nearby and having the opposite surface exposed; (c) extruding the drug, in gel form, into at least one exposed surface of the first or second adhesive laminates; and (d) laminating together the exposed surfaces of the first and second adhesive laminates such that the adhesive layers and the gelled drug combine to form an adhesive composite layer containing drug having the distant bottom layer material covering a surface of the same, and the next releasable release liner covering the opposite surface thereof.
In other words, the drug, in gel form and optionally containing reinforcing agents, preservatives, anti-oxidants, anti-irritants, cellulizing agents and the like can be extruded on any or both of the exposed surfaces of the first or second adhesive layers that are then laminated together to form an adhesive compound that contains the drug. A further aspect of the method is to protect the exposed surfaces of both the first and second adhesive layers during manufacture of the device with in-process release liners that are removed prior to extrusion of the gelled drug to the adhesive surface, and to laminate the exposed surfaces of the adhesive. the two adhesive layers to form the drug / adhesive compound. In this embodiment, the extrusion of the gelled drug can be done on any adhesive layer followed by lamination. In addition, if desired, the extraction of the gelled drug could also be done on both adhesive layers. Yet another aspect and more specific modality of the method is to manufacture the TDD devices for administering nicotine for therapy to stop smoking. The gelled nicotine is formulated by mixing with a gelling agent such as hydroxypropylcellulose. An antioxidant preservative, such as butylated hydroxytoluene, may also be added to the formulation.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 shows a partially schematic sectional view of a TDD device in accordance with the present invention. Figure 2 shows a partially schematic sectional view of a first laminated adhesive intermediate used to fabricate the TDD device of Figure 1. Figure 3 shows a partially schematic sectional view of a second laminated adhesive intermediate used to fabricate the device. TDD of Figure 1. Figure 4 shows a partially schematic sectional view of a completed TDD device in accordance with Figure 1, with the addition of a close overlapping release liner tab.
DETAILED DESCRIPTION OF THE INVENTION Before the present method for manufacturing transdermal and transmucosal drug delivery devices is disclosed and described.It should be understood that this invention is not limited to the steps and materials of the specific process disclosed herein since these process steps and materials may vary to some degree. It should also be understood that the terminology used herein is used for purposes of describing the specific embodiments only and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims. It should be noted that, as used in this specification and the appended claims, the singular forms of "a", "an", and "the" include multiple references unless the content clearly states the contrary. Thus, for example, the reference to a laminated structure containing "A drug" includes a mixture of two or more drugs, the reference to "an adhesive", includes reference to two or more of these adhesives, and the reference a "reinforcer" includes reference to a mixture of two or more reinforcers. In describing and claiming the present invention, the following terminology will be used in accordance with the definitions that will be noted below.
As used herein, the term "active gel", "gelled drug", "drug in gel form" and similar terms mean a drug in which a gelling agent is dispersed to obtain selected properties of flow and surface tension. for application to laminated patches. In this manner, the active gel is a liquid drug in a viscous state, however, effluent, and can be a colloidal / biphasic or dissolved mixture of the liquid drug and a gelling agent. The liquid drug means either a drug that in itself is a liquid or that dissolves, suspends or disperses in a solvent or selected vehicle. This solvent could be a liquid, such as ethanol, water and similar materials or a semi-solid of low viscosity that can be extruded, such as low molecular weight polymers, waxes, petroleum jelly and the like. The active gel may also include enhancers that may be added to the formulation to facilitate transport of the drug through the skin or mucosa to the body. The active gel may also include a combination of drugs, gelling agents, reinforcers, preservatives, anti-oxidants, anti-irritants, cellulization agents and the like. The term "gel" is intended to apply to the functional nature of the thickened drug component, whether or not the technical definition of a gel is satisfied. As used herein, the term "drug" or "pharmacologically active agent" or any of the other like terms means any chemical or biological material or compound that is suitable for transdermal or transmucosal administration by methods previously known in the art and / or by methods disclosed in the present invention, which induces a desired biological or pharmacological effect, which may include, but is not limited to (1) affecting living processes, (2) having a prophylactic effect on the organism and which prevents an undesired biological effect such as avoiding an infection, (3) alleviating a condition caused by a disease, for example, relieving pain or inflammation caused as a result of the disease and / or (4) either alleviating, reducing or completely eliminate the disease from the organism. The effect may be local, such as providing a local anesthetic effect, or it may be systematic. This invention is not related to novel drugs or new classes of active agents. Instead, it is limited to devices and methods for manufacturing these devices for the delivery of drugs or agents that exist in the art or that can be established subsequently as active drugs or agents and that are suitable for delivery by means of the present invention. These substances include broad classes of compounds normally delivered to the body, including through surfaces and membranes of the body, including in the skin and mucous membranes. In general, this includes but is not limited to: anti-infection agents, such as antibiotics and antiviral agents; analgesics and analgesic combinations; anorexics; anthelmintics; antiarthritic; antiasthmatic agents; anticonvulsants; antidepressants; antidiabetic agents; antidiarrheals; antihistamines; anti-inflammatory agents; preparations of antimigraine, antinauseabundos; antineoplastic; antiparkinsonism drugs; antipruritics; antipsychotics, antipyretics; antispasmodics; anticholinergic; sympathomimetics; xanthine derivatives, cardiovascular preparations, including potassium and calcium channel blockers, beta-blockers, alpha-blockers and antiarrhythmics; antihypertensive; diuretics and antidiuretics; vasodilators, including general coronary, peripheral and cerebral diseases; stimulants of the central nervous system; vasoconstrictors; cough and cold preparations, including decongestants; hormones, such as estradiol and other steroids, including corticosteroids; hypnotic agents; immunosuppressive; muscle relaxants; parasympatholytics; psychostimulants; sedatives, tranquilizers; and nicotine and acid addition salts thereof. The flow of a drug through the skin or mucosa can change either the resistance (the coefficient of dysfunction) or the driving force (the gradient for diffusion). Similarly, the flow of an analytical material (a chemical or biological material appropriate to pass through a biological membrane from which an individual may wish to know the concentration or activity within the body) through the skin or mucosa to collection or analysis on the outside of the body, can also be increased. The flow can be reinforced by the use of so-called penetration or chemical reinforcers, the chemical reinforcers comprise two categories of principal components, ie, cells and solvent enveloping alteration compounds or binary systems containing both the compounds that disrupt the envelope of cells like solvents. Compounds that disrupt the envelope of the cell are known in the art as being useful in typical pharmaceutical preparations and also function in the removal of the material to be analyzed through the skin. These compounds are thought to help penetrate the skin, disrupting the lipid structure of stratum corneum cell envelopes. A comprehensive list of these compounds is described in European Patent Application No. 43,338, published June 13, 1982, which is incorporated herein by reference. It is believed that any compound that disrupts the envelope of the cell is useful for purposes of this invention. The exemplary compounds that transforms the envelope of the cell are those represented by the formula:
R - X
wherein R is a straight chain alkyl of about 7 to 16 carbon atoms, a non-terminal alkenyl of about 7 to 22 carbon atoms, a branched chain alkyl of about 13 to 22 carbon atoms and X is sorbitan, glycerin , -OH; -COOCH2, -COOC2H5, -OCOCH3, -SOCH3, -P (CH3) 20, -COOC2H4OC2H4OH, -COOCH (CHOH) 4CH2OH, -COOCH2CHOHCH3, -COOCH2CH (OR ") CH2OR", - (OCH2CH2) mOH, -COOR1, or -CONR'2; wherein R 'is -H, -CH3, -C2H5, -C3H7 or -C2H4OH; R "is -H or a non-terminal alkenyl of about 7 to 22 carbon atoms, and m is 2 to 6, with the proviso that when R" is an alkenyl and X is -OH or -COOH, at least one double bond is in the cis configuration. Preferred cell envelope disorder compounds include de-myristate
isopropyl, methyl laurate, oleic acid, oleyl alcohol, glycerol monooleate, glycerol dioleate, glycerol trioleate, glycerol monostearate, glycerol monolaurate, propylene glycol monolaurate and sorbitan esters and mixtures thereof. Suitable solvents include water; diols, such as propylene glycol and glycerol; mono-alcohols, such as ethanol, propanol and higher alcohols; DMSO; dimethylformamide; N, N-dimethylacetamide; 2-pyrrolidone; N- (2-hydroxyethyl) pyrrolidone, N-methylpyrrolidone, 1-dodecylazacycloheptan-2-one and other n-substituted alkyl-azacycloalkyl-2-ones (azones) and the like. U.S. Patent No. 4,537,776, issued to Cooper, issued August 27, 1985, contains an excellent compendium of prior art and background information detailing the use of certain binary systems for permeation reinforcement. Due to the completeness of that disclosure, the information and terminology used therein are incorporated herein by reference. Similarly, European Patent Application No. 43 438, to which reference has been made above, discloses the use of diols selected as solvents together with a broad category of cell envelope disorder compounds for the supply of lipophilic pharmacologically active compounds. Due to the detail of disclosing the compounds that disrupt the cell envelope and the diols, this disclosure of European Patent Application No. 433838 is also incorporated herein by reference. A binary system for strengthening the penetration of metoclopramide is disclosed in UK Patent Application Serial No. GB 2,153,223 A, published on August 21, 1985, and consists of a monovalent alcohol ester of an aliphatic monocarboxylic acid of from 8 to 32 carbon atoms (unsaturated and / or branched if it is 18 to 32 carbon atoms) or an aliphatic monoalcohol of 6 to 24 carbon atoms (unsaturated and / or branched if it is 14 to 24 carbon atoms) and a compound N -cyclic, such as 2-pyrrolidone, N-methylpyrrolidone and the like. Combinations of reinforcers consisting of monoethyl ether and diethylene glycol monomethyl with monolaurate and propylene glycol methylillate are disclosed in US Patent Number 9,973,468, as reinforcing the transdermal delivery of the spheroids, such as progestogens and estrogens. A double enhancer consisting of glycerol monolaurate and ethanol for transdermal drug delivery is shown in U.S. Patent Number 4,820,720. U.S. Patent No. 5,006,342 lists numerous enhancers for transdermal drug administration consisting of fatty acid esters or fatty alcohol ethers of alkanediols of 2 to 4 carbon atoms, wherein each fatty acid / alcohol portion of the ester / ether is about 8 to 22 carbon atoms. U.S. Patent No. 4,863,970, shows penetration enhancing compositions for topical application comprising an active permeation material contained in a penetration enhancing vehicle containing specified amounts of one or more compounds that disrupt the envelope of the cell, such as oleic acid, oleyl alcohol, and glycerol esters of oleic acid; an alkanol of 2 or 3 carbon atoms and an inert diluent, such as water. Other chemical enhancers, not necessarily associated with binary systems, include DMSO or aqueous solutions of DMSO, as disclosed in Herschler's US Patent Number 3,551,554; Herschler's North American Patent Number 3,711,602; and the North American Patent Number of Herschler, Number 3,711,606, and the azones (n-substituted alkyl-azacycloalkyl-2-ones) as mentioned in Cooper's North American Patent Number 4,557,943.
Some chemical booster systems may possess negative side effects, such as toxicity and skin irritation, US Patent Number 4,855,298, discloses compositions for reducing skin irritation caused by compositions containing the chemical booster having irritating properties. of the skin with enough glycerin to provide an anti-irritant effect. Therefore, anti-irritants can advantageously be added to drug / reinforcer compositions within the scope of the invention. The solubility of certain drugs in some adhesives used in the adhesive laminates described herein can be disadvantageously low. Solubility enhancing agents, solubilizing agents or agents that alter solubility can be added in the drug formulation to improve the solubility of the drug and, therefore, the concentration of the drug in the adhesive laminates. Increasing the concentration of the drug in the adhesive laminates also increases the transdermal concentration or the transdermal flow. Examples of these solubilizing agents include solvents, such as lower chain alcohols, diols and triols, low molecular weight polymers, such as polyethylene glycol and polypropylene glycol and other substances suitable for increasing the solubility of the drug in the adhesive layers. The embodiments described in Figures 1 to 4 are presented with reference to nicotine as the active drug, however, it will be apparent to a person skilled in the art that any other liquid drug contained in an active gel that can be delivered transdermally or transmucosally. it can be replaced instead of nicotine. It should be emphasized that the present invention is particularly suited to the formulation of drugs, enhancers or other formulation ingredients that are volatile or heat sensitive and that can not be easily formulated under conditions where elevated temperatures are required. Since the terms "volatile" or "heat sensitive" can be considered as being relative for the purposes of drug definition herein, the enhancers or other ingredients of the formulation are considered "volatile" or "heat sensitive" when they have a melting temperature, decompose or deactivate at less than 100 ° C, particularly at less than about 75 ° C and particularly preferably at less than about 50 ° C. Referring to Figure 1, the TDD device that is provided by the present method is generally shown at 10. The device 10 is in the form of an adhesive composite layer containing a laminated drug adapted to adhere to a predetermined area of the skin or tissue of intact mucosa. The individual layers of the device 10 include a bottom layer 14 that is essentially impermeable to the drug, a drug-laden adhesive compound 18 that is adapted to adhere to the skin or mucosa, and a near-release liner 22 essentially impermeable to the drug. . The adhesive composite 18 consists of a distant adhesive layer 19, a proximal adhesive layer 20 and a layer 21 of gelled drug, placed therebetween. These layers will be described in greater detail below. The distant bottom layer 14 in use defines the side of the patch that faces the environment, i.e., distant from the skin or mucosa. The functions of the bottom layer 14 are to protect the patch and provide an impenetrable layer that prevents the loss of nicotine (or other liquid or volatile drug) into the environment. Therefore, the selected material must be resistant to nicotine and must be minimally permeable to nicotine. Advantageously, the material of the bottom layer can be opaque to protect the nicotine from degradation of its exposure to ultraviolet light. further, the bottom layer 14 must be able to bind to and hold the other layers of the device, but nevertheless, it must be flexible to accommodate the movements of a person using the device 10. A preferred material is aluminized polyester or polyester, by example, medical polyester films such as those sold under the names Scotchpak (R) 1009 or 1109 of 3M Corporation. Aluminized polyester has a nicotine permeability of less than about 0.2 microgram • 100 micrometers / square centimeter * hour. There are limited materials that are sufficiently impermeable to nicotine to retain the nicotine load properly during storage or use. However, other low permeability materials that can be used with or without modification are those that are selected from the group consisting of thin sheets of metal, thin metallized foils, composite thin foils or polyester-containing films such as polyester terephthalate, type of polytetrafluoroethylene ("TEFLON (R)") or equivalents thereto, polyether block amide copolymers (e.g., "PEBAX" copolymers), polyethylene methyl methacrylate block copolymers, such as the "NUKRELL" polymers ™ ", polyurethanes, such as polymers
"PELLATHANE ™" or "TINY ™", polyvinylidene chloride
(Saran (R)), nylon, silicone elastomers, rubber-based polyisobutylene, styrene, copolymers of styrene and butadiene and styrene and isoprene, polyethylene and polypropylene. Although many of these materials were mentioned by US Pat. No. 4,943,435, issued to Baker, as being unsuitable for use with nicotine, it is considered that, when formulated in the manner described herein, the materials listed are sufficiently resistant to degradation by nicotine to be useful in the presently described invention. A thickness of about .0254 to .1016 millimeter is preferred, with one of .0508 to .0762 millimeter being more preferred. The adhesive (s) used to form the adhesive / drug compound 18 must be compatible with nicotine and allow a useful flow of nicotine. The next and distant adhesive layers 19 have leading roles in determining the rate at which the nicotine is released from the device 10. The material comprising the adjacent adhesive layer 20 is a contact adhesive with the pressure-sensitive skin consisting of a pharmaceutically acceptable material. It must also meet the general criteria for adhesives used for transdermal patches, including biocompatibility, ease of application and ease of removal. The adhesives in both adhesive layers close to 20 and distant 19 are preferably made of materials in which nicotine has moderate diffusivity. After equilibration, the substance will have diffused through the adhesive compound 18, which is useful for regulation of the release kinetics. Therefore, by careful selection of the materials used for the adhesive compound 18, the distribution of nicotine throughout the system can be regulated. Another useful criterion includes suitable drug solubility in the adhesive layers to provide deposition capacity. Preferably, the adhesive compound 18 has a thickness within the range of about .0254 to .508 millimeters, more preferably of .0508 to .254 millimeters, and especially preferably of .0508 to .1270 millimeters. Adhesives suitable for use in the practice of the invention include an acrylic adhesive such as that sold under the factory names RA2484, RA2333, RA2397, R363 and R362 of Monsanto Co.; other acrylic adhesives, such as DUROTAK (R> 80-1196 (National Starch, crosslinked or non-crosslinked acrylic copolymer), SP18305 ™ (Avery International), MSX435 ™ (3M) and "NEOCRYL ™" (Polyvinyl Chemicals, Ltd.) : vinyl acetate adhesives, such as Flexcryl ™ -1614, -1617, -1618 and -1625 from Air Products, and natural and synthetic rubbers including polyisobutylenes, neoprenes, polybutadienes and polyisoprenes Other suitable materials include ethylene and acetate copolymers of vinyl, polysiloxanes, polyacrylates, polyurethanes and polyamide block thymid copolymers of plasticized weight (copolymers "PEBAX"). As in the case of bottom layer materials, some of these materials were disclosed in the Patent North American Number 4,943,435, granted to Baker as having been dissolved, attacked or degraded by nicotine, however, the results indicated that when properly formulated in accordance with the present inv. tion, are suitable materials for manufacturing delivery devices containing nicotine. The adhesives comprising the distant adhesive layer 19 and the adjacent adhesive layer 20 may be the same or different. If they are different, a selection of the adhesives can be used to control or regulate the dissolution of the drug within the adhesive compound. For example, if the drug is more soluble and permeable in the adhesive comprising the distant layer 19 than the adhesive comprising the next layer 20, then the adhesive comprising the next layer 20 could be a rate limiting agent in terms of diffusion of the drug outside the device 10 to the surface of the skin or mucosa. The thicknesses of the distant layers 19 and next 20, may also be selected to provide desired amounts of storage capacity and diffusion regulation. If the drug is more soluble and permeable in the next layer, then it is possible to provide a rapid release of a selected amount of the drug from the proximal layer 20 and a sustained release of the distant layer 19 from a selected amount of the drug to through a selected period of time. Another possible arrangement is that either the layer 19 distant to the next layer 20 or both are a composite. For example, if the proximal layer 20 is a compound of a proximal stratum wherein the drug is very soluble and permeable and a stratum distant where the drug is less soluble and permeable and the distant layer 19 comprises of a polymer in which the The drug is very soluble and permeable, the drug is rapidly released from the near stratum of the next layer with release from the distant layer 19 regulated by the regime limiting properties of the distant stratum of the next layer 20. A person skilled in the art will be able to devise other useful arrangements based on these principles. The proximal release liner 21 covers the skin lining or proximal side of the TDD device 10 until the device 10 is used. Therefore, the proximal release liner 22 must possess the same properties as those of the background layer. 14 and the same materials are preferred. Just prior to the use of the device, the proximal release liner 22 is removed to expose the nicotine-containing adhesive composite layer 18 for contact and addiction with the surface of the skin or mucosa. As will be seen in the following description, the adhesive 18 containing the drug is actually a composite formed by joining two adhesive layers after the deposition of the nicotine, in the form of a gel, towards the surface of at least one of them. The adhesives that form each layer can be the same or different but must be compatible with each other and must be able to absorb nicotine, but allow it to diffuse from the adhesive to the skin or mucosa, at an acceptable flow rate . ACTIVE GEL Nicotine is a critalin liquid that has approximately the same viscosity as water. However, the extrusion coating requires a viscous fluid, influencing the viscosity of the coating regime and the deposition accuracy. Preferably, the vision is within the range of about 1,000 to 200,000 centipoise, more preferably within the range of about 1,000 to 50,000 centipoise, and especially preferably within the range of about 2,000 to 20,000 centipoise. In order to effectively expel nicotine into the fiber layer of a controllable material, such as, for example, through an extrusion die matrix, the drug must be thickened to an acceptable viscosity. Hydroxypropylcellulose ("HPC"), a water-soluble polymer obtainable in pharmaceutical grade form, is a preferred gelling agent that can be added to nicotine to increase its viscosity. The HPC fulfills the requirements of the National Form for heavy metal levels. The HPC is added to the nicotine, preferably within the range of about 1 percent to 5 percent (w / w), most preferably, within the range of about 2 percent to 4 percent (by weight / weight), and especially preferably, within the range of approximately 2.5 to 3.5 percent
(in weight / weight). A source of HPC, particularly preferred is Aqualon (Wilmington, Delaware), which sells the
HPC under the factory name KLUCEL (R). Other gelling agents, such as an acrylic polymer thickener, can also be advantageously used.
[AMSCO 6038 ™ (Unocal)], methyl cellulose, hydroxymethyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, low molecular weight polymers, petroleum jelly and the like.
Another feature of nicotine that can be problematic is its tendency to oxidize easily in the presence of light and air. To avoid oxidation during storage, nicotine should be kept in a dark container and preferably in a dark cabinet. Flooding the storage vessel with an inert gas such as nitrogen also reduces oxidation. During the manufacture of nicotine patches, oxidation is controlled by the addition of an antioxidant to the active gel. A preferred antioxidant is butylated hydroxytoluene (BHT). The BHT is mixed with the nicotine, preferably within the range of about 0.01 percent to 1.0 percent (w / w), most preferably, within the range of about 0.03 percent to 0.3 percent (by weight / weight), and especially preferably, within the range of about 0.05 percent to 0.2 percent (in weight / weight). Other suitable antioxidants include butylated hydroxyanisole (BHA), sodium metabisulfate, maleic acid, EDTA, cysteine hydrochloride and alpha-tocopherol. The active gel is prepared by adding HPC to the nicotine, while stirring, taking care to avoid agglomeration of the gel. The BHT is added and mixed with stirring as well. Then, the mixture of nicotine, HPC and BHT is hermetically sealed in a container and mixed for a prolonged period of time to ensure that the gelling agent has completely dissolved and that the mixture is homogeneous.
EXAMPLE 1
Active gel was prepared by combining 96.9 percent (w / w) nicotine in the free base form, 3.0 percent (w / w) HPC (KLUCEL GF ™, a low molecular weight form of HPC having a molecular weight of approximately 370,000) and 0.1 percent (by weight / weight) of BHT at room temperature. These components were mixed for 26.5 hours in a roller mill and then the active gel was stored under a nitrogen atmosphere. PRIMARY INTERMEDIATE ADHESIVE LAMINATION Figure 2 shows a primary intermediate adhesive laminate 26 used in the manufacturing process of the TDD devices 10 shown in Figure 1. This pre-primary intermediate laminate 26 is composed of a waterproof bottom layer 14, an adhesive layer 19 and a release liner 30 in process. The bottom layer 14 is the same bottom layer 14 that forms the exterior or the distant coating of the TDD device, as shown in Figure 1 and which has already been described. The adhesive 19 has also been described in relation to the drug-end adhesive compound 18 of the finished device 10 of Figure 1 and comprises the distant adhesive layer 19 in the finished device 10. The thickness of the adhesive layer 19 in the primary intermediate adhesive laminate 26 is only a part or portion of the thickness of the composite 18 of the loaded adhesive (Figure 1) of the device 10 once it is manufactured as a TDD, since the adhesive layer 19 of the laminate 26 primary intermediate adhesive and the adhesive layer 20 of a laminate 34 secondary intermediate adhesive
(which is described with reference to Figure 3) are laminated together with the gelled drug to form the adhesive compound 18 containing drug from device 10 (Figure 1).
In the preferred manufacturing mode, the process release liner 20 is laminated to the adhesive layer 19 during the manufacture of the primary intermediate 26, but is removed again as part of the process for manufacturing the device 10. Under certain circumstances, however, eg, when the adhesive layer 19 can be adequately protected, the in-process release liner 30 can be omitted from the manufacturing process of the TDD. The process release liner 30 may be composed of any of the materials described for the proximal release liner 22 of Figure 1. However, as will be briefly described, the in-process release liner 30 never comes in contact with nicotine , therefore, it does not need to be manufactured from a material that is resistant to nicotine degradation or permeation. The primary intermediate adhesive laminate 26 can be manufactured in a coating machine using any number of established processes. One of these processes is slot die extrusion, wherein a thin uniform film of a molding solution is extruded into the bottom layer material. A preferred embodiment of this process, the molding solution, a liquid formulation of adhesive material in an appropriate solvent, is pumped into an extrusion slot die at a controlled rate to a release liner 30 forming a "coated continuous ribbon" which It has an adhesive surface. Then, the continuous coated tape or the continuous roll of the release liner coated with adhesives is passed through a drying oven where excessive solvents are removed from the coating or adhesive layer 19. The film 14 of the bottom layer is then laminated to the exposed surface of the molding or drying adhesive 19 in the release liner 30 thereby completing the formation of the primary laminate 26, which is then rolled into a roll. The optimum coating parameters can be determined, independently of the selected adhesive.
The full adjustment capacity, the flow of the molding solution and the drying parameters allow this process to be used in a variety of different adhesive types. The adhesive does not contain the drug at this point in the process. An alternative for extruding the molding solution into the liner 30 is to extrude the molding solution to the bottom film 14.
EXAMPLE 2
A primary intermediate adhesive laminate 26 was made with an acrylic adhesive coating 19. The acrylic adhesive (National Starch 80-1196) was dissolved in a solvent to form a molding solution consisting of 45 percent adhesive, 8.25 percent ethyl acetate, 25.30 percent isopropyl alcohol, 2.75 percent toluene and 18.70 percent heptane. The molding solution was extruded by slot die extrusion to the silicon polyester light release liner 30 (Reléase Technologies 3EST-A-S242M) in a two zone coating / drying / laminating machine. The heating zones inside the drying oven of the machine were at a temperature of 80 ° C and 100 ° C and the speed was graduated at 1.83 meters per minute. The laminate or drying, i.e., the adhesive 19 and the release liner 30 was then covered with a Scotchpak (R) 1109 (3M) meat-colored background film and re-rolled for later use. SECONDARY INTERMEDIATE ADHESIVE LAMINATION In Figure 3, the secondary intermediate adhesive laminate 34 is shown as being constructed of a laminated adhesive layer 20 between the in-process release liner 30 and the proximal release liner 22. All these components have been described above. The secondary intermediate adhesive laminate 34 is manufactured in a manner similar to that of the primary intermediate adhesive laminate 26. An adhesive molding solution 20 is coated, by slot die extrusion, to a release liner 22 and then dried. Then, instead of laminating a bottom film as the primary intermediate, a release liner 30 is laminated in process in the structure of the adhesive release liner. MANUFACTURE OF ACTIVE LAMINATE The active laminate 10 of TDD is manufactured from the active gel and two intermediate laminates 26 and 34 that have been described above. The process release liners 30, if present, are pulled away from each of the primary laminates 26 and 34 secondary. The gelled drug is then extruded into the adhesive layer, either from the primary intermediate 26 or secondary laminate 34 and the laminates are pressed together to bond the adhesive layers 19 and 20 and the gelled drug layer 21 to the adhesive compound 18. Alternatively, the gelled drug can be extruded to the point of attachment of the lamination between the adhesive layers 19 and 20 as they are laminated together to form the adhesive compound. In any procedure, the result is an active laminate. After the active laminate 10 has been manufactured, patches are cut to the desired size and shape. Exemplary of a suitable means for this purpose is a rotary die cutter, such as the normal matrix cutting machine Webtron 650. The active laminate 10 can be cut into patches of virtually any size, depending on the requirements of the dosage. The laminate 10 is placed in the die cutter, where the release liner 22 covering the adhesive compound 18 is peeled off. Instead of the release liner 22, narrow strips of the material of the release liner were re-laminated to the surface of the adhesive. As shown in Figure 4, the narrow strips overlap slightly to form a small tab 36 for easy release of the release liner during use. The cut pattern is generally centered above the overlap of the narrow release liner strips, so that the tab 36 is centered on the patch. This type of release liner is considered equivalent to the release liner used in initial manufacturing because both carry out the same functions of protecting the adhesive layers of the TDD device and of retaining the drug within the device. In this way, removing one release liner and replacing it with another is within the scope of the invention. Therefore, the term "release liner" and / or "peelable film" are intended to encompass any and all embodiments of the liners and / or protective films. The resulting patches are then thermally sealed in bags.
EXAMPLE 3
An active laminate 10 of 2 intermediates 26 and 34 that have been described above was made using a coating / laminating machine. The secondary intermediate adhesive laminate 34 was fed through the machine, such that the release liner in process was peeled off exposing the distal surface of the adhesive layer 20 and the continuous tape of the release liner 22. The active nicotine gel was applied to the adhesive layer 20 by extrusion through a slot matrix. The gelled drug was pumped into the slot matrix and extruded to the adhesive surface with a Zenith gear pump (0.066 milliliter / revolution capacity). The release liner 30 of the primary intermediate adhesive laminate 26 was peeled off from the adhesive layer 19 and the remaining backing / adhesive layer film (19 and 14) of the primary intermediate adhesive laminate 26 was laminated to the adhesive layer 20 coated with the gel. active of laminate 34 secondary intermediate adhesive to form an adhesive compound. The weight of the adhesive resulting from the laminate sandwich was 16.2 milligrams per square centimeter. The drug content of the active laminate was tested at 1.98 milligrams of nicotine per square centimeter. This active laminate 10 was stored in a thin metal foil pouch and protected from light to minimize the loss of the drug. The active laminate 10 was patched and sealed in bags as quickly as possible after the manufacture of the active laminate. The release liner 22 was removed from the active laminate 10 and replaced with narrow overlapping strips of the release liner material so that the tabs 36 so as to form tabs 36 for easy removal of the release liner 22. Active patches of 10 square centimeters were cut from the active laminate using a rotary die cutting machine with normal die tools. The patches were inspected after cutting and thermally sealed in bags with thin aluminum foil lined with polyethylene. The completed patches were tested and found to contain 1.96 milligrams per cubic centimeter of nicotine.
EXAMPLE 4
Nicotine patches were prepared by extruding the nicotine gel directly to the lamination holding point while the adhesive surfaces 19 and 20 were laminated together. The nicotine gel was prepared as described in Example 1 and extruded to the lamination holding point using a syringe pump at a rate of 180 milligrams per minute. The loading of the drug was varied by changing the linear rolling speed from 4.88 meters to 12.19 meters per minute. The nicotine-coated adhesive laminates were then stored in bags lined with thin metallic paper. The patches (10 square centimeters) were cut with a die using a rotary die cutter and sealed in polyethylene lined thin paper protective bags, as described above. Nicotine patches were tested to determine the nicotine content and the results are presented in Table 1.
TABLE 1
LAMINATED NICOTINE CONCENTRATION * NUMBER (MILIGRAMO / GRAM)
101 63.64
102 73.77
103 94.15
104 109.06
105 130.90
* The concentration is expressed as milligrams of nicotine per gram of the adhesive laminate.
EXAMPLE 5 Skin flow studies were carried out in vi tro using modified Franz diffusion cells. A human epidermal membrane thermally separated from the entire skin of a cadaver of a human was prepared by the method of Klingman and Christopher, 88 Arch. Dermatol. 702 (1963). The total thickness of the skin was exposed to heat of 60 ° C for 60 seconds, after which the stratum corneum and part of the epidermis (epidermal membrane) were gently detached from the dermis. The epidermal membrane and the nicotine patches were cut into pieces of 1 square centimeter. After removing the next release liner, the matrix of the adhesive containing exposed nicotine was laminated to the surface of the stratum corneum of the epidermal membrane. The sandwich of the skin / adhesive matrix was then placed in the diffusion cell with the epidermal side facing the receiving compartment and held in place. The receptor compartment was then filled with a citrate / phosphate stabilizer of pH 4.0. The cell was then placed in a calibrated circulation water bath to maintain the surface temperature of the skin at 32 + 1 ° C. At predetermined time intervals, all contents of the receptor compartment were collected for nicotine quantification, and the receptor compartment was refilled with fresh citrate / phosphate stabilizer taking care to remove air bubbles at the skin interface. stabilization agent. The cumulative amount of the drug that penetrated per unit area for any time t (Q ^, microgram / square centimeter) was determined according to the following equation:
t Qt = £} (cn * v) n = 0 A where Cn is the concentration (microgram / milliliter) of the drug in the corresponding time receiver sample, V is the volume of fluid in the receiving chamber (~ = 6.3 square centimeters) and A is the area of diffusion of the cell (0.64 square centimeter). The inclination of the straight line to the line Q ^ v.t provides the constant state flow (Jss' microgram / square centimeter / hour). The results of the skin flow in vi tro of the active laminates prepared in Example 4, are presented in Table 2. The flow of the nicotine skin increased linearly with the loading of the drug, as shown in Figure 5. The equation of the line is y = -31.505 + 0.71447x and the correlation coefficient R2 = 0.987.
TABLE 2
NUMBER CONCENTRATION IN VITRO FLOW NUMBER OF NICOTINE (ug / cm2 / h) OF LAMINATE (mg / g) * SKINS
101 63.64 16.45 + 3.99
102 73.77 20.20 + 3.57
103 94.15 33.84 + 5.25
104 109.06 44.61 + 8.05
105 130.90 64.26 + 12.74
* Concentration is expressed as milligrams of nicotine per gram of adhesive laminate.
EXAMPLE 6
An active albuterol laminate containing a volatile booster formulation was prepared using the techniques described in Example 2 and using a clear bottom film (Scotchpak 1012, 3M). The reinforcer consisted of a mixture of ethanol / water / glycerol monooleate / methyl laurate / lauryl alcohol in volume ratios of 70/15/5/5/5. The free base of albuterol was dissolved in the booster at a final concentration of 100 milligrams per milliliter. The pH was adjusted to a pH of 5.5 with acetic acid and the mixture was gelled with 2 percent HPC (Klucel GF). The active gel was extruded between the adhesive layers to form an active laminate. The active laminate was immediately cut with matrix in patches of 5 square centimeters and sealed in thin paper bags lined with polyethylene metal. The content of albuterol was tested at 4.14 + 0.29 milligrams per patch. The skin flow in vi tro determined as described in Example 5 was determined to be 0.2 micrograms per square centimeter per hour. Although the foregoing examples and description demonstrate the formation of an active nicotine laminate suitable for transdermal delivery, the same techniques can be used to deliver other permeation materials or active drugs through the skin or mucosa. Therefore, the aforementioned examples are only illustrative of a complete and preferred embodiment that can be employed in the operation of the present invention. The invention is directed to the discovery that the appropriate formulation of various volatile and / or heat-sensitive drugs can be formulated in the transdermal and transmucosal delivery devices to be delivered to the stratum corneum or mucosa of a human or other animal. Therefore, within the guidelines presented herein, a certain number of experiments to obtain the optimum formulations can be carried out easily by those skilled in the art. Therefore, the invention is limited in scope only by the following claims and functional equivalents thereof.
Claims (60)
1. A method for manufacturing in a transdermal or transmucosal drug delivery device that includes an adhesive composite layer containing the drug having a drug-distant background material laminated to the distant surface of the composite layer and a nearby release film , which is essentially impermeable to the drug and which is adapted for removal to deliver a drug to the skin or mucosa laminated to the proximal surface of the composite layer, the method comprises the steps of: (a) providing a first adhesive laminate comprising a first adhesive layer permeable to the drug and having laminated on a surface thereof the material of the distant bottom layer and having the opposite surface of the first exposed adhesive layer; (b) providing a second adhesive laminate comprising a second adhesive layer having laminated on one surface thereof, the next peelable film and having the surface opposite the second exposed adhesive layer; (c) extruding the drug, in gel form, into at least one exposed surface of the first or second adhesive laminate; and (d) laminate together the exposed surfaces of the first adhesive laminate and the second adhesive laminate, at least one of which contains the extruded gelled drug, such that the first and second adhesive layers and the gelled drug are combined to form the composite adhesive layer containing drug having the distant bottom material covering a surface thereof and the next release film covering the opposite surface thereof.
The method according to claim 1, wherein the extrusion of the gelled drug and the lamination together with the exposed surfaces of the laminates is a continuous process.
3. The method according to claim 2, wherein the extrusion and lamination steps occur essentially simultaneously.
4. The method according to claim 1, wherein the drug has a melting temperature, is decomposed or deactivated at a temperature of less than about 100 ° C.
5. The method according to claim 4, wherein the temperature is less than about 75 ° C.
6. The method according to claim 1, wherein the drug is nicotine or an acid addition salt thereof.
The method according to claim 6, wherein the drug is a nicotine base.
The method according to claim 1, wherein the drug is gelled by the addition of a small amount and a member selected from the group consisting of hydroxypropylcellulose, hydroxymethylcellulose, methylcellulose and an acrylic-type thickener.
The method according to claim 8, wherein the adhesive comprising the first and second adhesive layers is a member selected from the group consisting of acrylics, vinyl acetates, natural and synthetic rubbers, ethylene vinyl acetate copolymers , polysiloxanes, polyacrylates, polyurethanes, polyether block amide copolymers of plasticized weight and mixtures thereof.
The method according to claim 9, wherein the adhesives comprising the first and second adhesive layers are different.
The method according to claim 10, wherein the drug has greater permeability in the adhesive comprising the first adhesive layer than in the adhesive comprising the second adhesive layer, thereby making the second adhesive layer limit the regime as for the diffusion of the drug out of the device towards the skin or mucosa.
The method according to claim 10, wherein the drug has greater permeability in the adhesive comprising the second adhesive layer than in the adhesive comprising the first adhesive layer, thereby providing a rapid release of the drug from the second adhesive layer and sustained release from the first adhesive layer.
13. The method according to claim 10, wherein at least one of the members of the group consisting of the first adhesive layer and the second adhesive layer comprises a composite adhesive layer having a proximal adhesive layer and a distant adhesive layer, wherein the adhesives comprising the next layer and the distant stratum have different permeabilities for the drug, thus affecting the supply of the drug through the device.
The method according to claim 9, wherein the adhesives consisting of the first and second adhesive layers are the same.
15. The method of confommation with claim 14, wherein the adhesive is selected from the group consisting of crosslinked and non-crosslinked acrylic copolymers.
16. The method according to claim 9, wherein the gelled drug also contains an antioxidant.
The method according to claim 3, wherein the gelled drug includes a member of the group consisting of penetration enhancers, anti-irritants and solubilization agents.
18. The method according to claim 17, wherein the gelled drug includes a penetration enhancer to facilitate transport of the drug through the skin or mucosa.
19. The method according to claim 18, wherein the penetration enhancer is a member selected from the group consisting of an organic solvent and a compound that disrupts the envelope of the cell and mixtures thereof.
The method according to claim 19, wherein the organic solvent is a member selected from the group consisting of water, diols, alkanols of 1 to 3 carbon atoms, DMSO, dimethylformamide, N, N -dimethylacetamide, 2-pyrrolidone, N- (2-hydroxyethyl) pyrrolidone, N-methylprirrolidone, l-alkylacylcycloheptan-2-ones and l-arylazacycloalkyl-2-ones, and the compound that disrupts the cell envelope is a member that is selected from the group consisting of isopropyl myristate, methyl laurate, oleic acid, oleyl alcohol, glycerol monooleate, glycerol dioleate, glycerol trioleate, glycerol monostearate, glycerol monolaurate, propylene glycol monolaurate and sorbitan esters.
21. A transdermal or transmucosal drug delivery device that includes a layer of the drug-containing adhesive compound having a distant background material impermeable to the drug laminated on the distant surface of the composite layer, and a release film that is essentially impermeable to the drug, adapted to be removed for administration of a drug to the skin or mucosa laminated on the proximal surface of the composite layer, the adhesive composite layer containing drug is formed by a method consisting of the steps of: (a) providing a first adhesive laminate comprising a first adhesive layer permeable to the drug having laminated a surface thereof, the distant bottom material and having the opposite surface of the first exposed adhesive layer; (b) providing a second adhesive laminate comprising a second adhesive layer having laminated on one surface thereof the next peelable film and having the opposite surface of the second adhesive layer exposed; (c) extruding the drug in the form of a gel towards at least one exposed surface of the first or second adhesive laminate; and (d) laminating together the exposed surfaces of the first adhesive laminate and the second adhesive laminate, at least one of which contains the gelled drug extruded such that the first and second adhesive layers and the gelled drug combine to form the adhesive composite layer containing drug and having the distant bottom material covering a surface thereof, and the next release film covering the opposite surface thereof.
22. The device according to claim 21, wherein the extrusion of the gelled drug and the lamination of the exposed surfaces of the laminates from one another is a continuous process.
23. The device according to claim 22, wherein the extrusion and lamination steps occur almost simultaneously.
24. The device according to claim 21, wherein the drug has a melting temperature, is decomposed or deactivated at a temperature of less than about 100 ° C.
25. The device according to claim 24, wherein the temperature is less than about 75 ° C.
26. The device according to claim 21, where the drug is nicotine or an acid addition salt thereof.
27. The device according to claim 26, wherein the drug is a nicotine base.
The device according to claim 21, wherein the drug is gelled by the addition of a small amount of a member selected from the group consisting of hydroxypropylcellulose, hydroxymethylcellulose, methylcellulose and an acrylic-type thickener.
29. The device according to claim 28 wherein the adhesive comprises the first and second adhesive layers and is a member selected from the group consisting of acrylics, vinyl acetates, natural and synthetic rubbers, ethylene vinyl acetate copolymers , polysiloxanes, polyacrylates, polyurethanes, polyether block amide copolymers of plasticized weight and mixtures thereof.
30. The device according to claim 29, wherein the adhesives comprising the first and second adhesive layers are different.
The device according to claim 30, wherein the drug has greater permeability in the adhesive comprising the first adhesive layer, than in the adhesive comprising the second adhesive layer, thereby making the second adhesive layer limit the regimen regarding the diffusion of the drug out of the device towards the skin or mucosa.
32. The device according to claim 30, wherein the drug has greater permeability in the adhesive comprising the second adhesive layer than in the adhesive comprising the first adhesive layer, thereby providing rapid release of the drug from the second adhesive layer and sustained release from the first adhesive layer.
The device according to claim 30, wherein at least one of the members of the group consisting of the first adhesive layer and the second adhesive layer comprises a composite adhesive layer having a close adhesive layer and a distant adhesive layer. wherein the adhesives comprising the proximal stratum and the distant stratum have different permeabilities with respect to the drug thereby affecting the delivery of the drug by the device.
34. The device according to claim 29, wherein the adhesives comprising the first and second adhesive layers are the same.
35. The device according to claim 34, wherein the adhesive is selected from the group consisting of crosslinked and non-crosslinked acrylic copolymers.
36. The device according to claim 29, wherein the gelled drug also contains an anti-oxidant.
37. The device according to claim 23, wherein the gelled drug includes a member of the group consisting of penetration enhancers, anti-irritant agents and solubilizing agents.
38. The device according to claim 37, wherein the gelled drug includes a penetration enhancer to facilitate transport of the drug through the skin or mucosa.
39. The device according to claim 38, wherein the penetration enhancer is a member selected from the group consisting of an organic solvent and a compound that disrupts the envelope of the cell and mixtures thereof.
40. The device according to claim 39, wherein the organic solvent is a member selected from the group consisting of water, diols, alkanols of 1 to 3 carbon atoms, DMSO, dimethylformamide, N, N-dimethylacetamide, 2-pyrrolidone, N- (2-hydroxyethyl) pyrrolidone, N-methylpyrrolidone, 1-alkylazacycloheptan-2-ones and l-arylazacycloalkyl-2-ones and the compound that disrupts the envelope of the cell is a member selected from the group which consists of isopropyl myristate, methyl laurate, oleic acid, oleyl alcohol, glycerol monooleate, glycerol dioleate, glycerol triolate, glycerol monostearate, glycerol monolaurate, propylene glycol monolaurate and sorbitan esters.
41. A method for delivering a drug through the skin or mucosa of a person comprising: (a) providing a transdermal or transmucosal drug delivery device including an adhesive composite layer containing drug and having a distant background material waterproof for the drug laminated on the distant sce of the composite layer, and a nearby release film which is essentially impermeable to the drug, adapted for removal to deliver a drug to the skin or mucosa laminated on the proximal sce of the composite layer, the layer adhesive composite containing drug being formed by a method comprising the steps of: (1) providing a first adhesive laminate comprising a first adhesive layer permeable to the drug having a sce of the same the distant bottom material laminated thereon, and has the opposite sce of the first adhesive layer exposed; (2) providing a second adhesive laminate comprising a second adhesive layer having laminate on a surface thereof, the proximate, projected film and having the exposed surface of the second adhesive layer exposed; (3) extruding the drug, in the form of a gel, towards at least one exposed surface of the first or second adhesive laminate; (4) laminate together with the exposed surfaces of the first adhesive laminate and the second adhesive laminate, at least one of which contains the extruded gelled drug, such that the first and second adhesive layers and the gelled drug combine to form the composite adhesive layer containing drug having the distant bottom material covering a surface thereof, and the next release film covering the opposite surface thereof; (b) removing the next peelable film from the device and placing the skin or mucosa in contact with the proximal surface of the adhesive composite layer.
42. The method according to claim 41, wherein the extrusion of the gelled drug and the rolling together of the exposed surfaces of the laminates is a continuous process.
43. The method according to claim 42, wherein the extrusion and lamination steps occur essentially simultaneously.
44. The method according to claim 41, wherein the drug has a melting temperature, is decomposed or deactivated at a temperature of less than about 100 ° C.
45. The method according to claim 44, wherein the temperature is less than about 75 ° C.
46. The method according to claim 41, wherein the drug is nicotine or an acid addition salt thereof.
47. The method according to claim 46, wherein the drug is a nicotine base.
48. The method according to claim 41, wherein the drug is gelled by the addition of a small amount of a member selected from the group consisting of hydroxypropylcellulose, hydroxymethylcellulose and an acrylic-type thickener.
49. The method according to claim 48, wherein the adhesive comprising the first and second adhesive layers is a member selected from the group consisting of acrylics, vinyl acetates, natural and synthetic rubbers, acetate copolymers, ethylene vinyl, polysiloxanes, polyacrylates, polyurethanes, plasticised polyester block amide copolymers and mixtures thereof.
50. The method according to claim 49, wherein the adhesives comprising the first and second adhesive layers are different.
51. The method according to claim 50, wherein the drug has greater permeability in the adhesive comprising the first adhesive layer than in the adhesive comprising the second adhesive layer, thereby making the second adhesive layer limit the regime as for the diffusion of the drug out of the device towards the skin or mucosa.
52. The method according to claim 50, wherein the drug has greater permeability in the adhesive comprising the second adhesive layer than the adhesive comprising the first adhesive layer, thereby providing rapid release of the drug from the second adhesive layer. adhesive layer and sustained release from the first adhesive layer.
53. The method according to claim 50, wherein at least one of the members of the group consisting of the first adhesive layer and the second adhesive layer comprises a composite adhesive layer having a close adhesive layer and an adhesive layer. distal, wherein the adhesives comprising the proximal stratum and the distant stratum have different permeabilities for the drug, thereby affecting the delivery of the drug by the device.
54. The method according to claim 49, wherein the adhesives comprising the first and second layers are the same.
55. The method according to claim 54, wherein the adhesive is selected from the group consisting of crosslinked and non-crosslinked acrylic copolymers.
56. The method according to claim 49, wherein the gelled drug also contains an anti-oxidant.
57. The method according to claim 43, wherein the gelled drug includes a member of the group consisting of penetration enhancers, anti-irritant agents and solubilizing agents.
58. The method according to claim 57, wherein the gelled drug includes a penetration enhancer to facilitate transport of the drug through the skin or mucosa.
59. The method according to claim 58, wherein the penetration enhancer is a member selected from the group consisting of an organic solvent and a compound that disrupts the envelope of the cells and mixtures thereof.
60. The method according to claim 59, wherein the organic solvent is a member selected from the group consisting of water, diols, alkanols of 1 to 3 carbon atoms, DMSO, dimethylformamide, N, N-dimethylacetamide, 2-pyrrolidone, N- (2-hydroxyethyl) pyrrolidone, N-methylpyrrolidone, 1-alkylazacycloheptan-2-ones and l-arylazacycloalkyl-2-ones and the compound that disrupts the envelope of the cells is a member selected from the group which consists of isopropyl myristate, methyl laurate, oleic acid, oleyl alcohol, glycerol monooleate, glycerol dioleate, glycerol trioleate, glycerol monostearate, glycerol monolaurate, propylene glycol monolaurate and sorbitan esters. SUMMARY OF THE INVENTION A method for manufacturing a transdermal drug delivery device for heat sensitive and volatile drugs is disclosed. The device contains a composite adhesive layer containing the drug having a waterproof bottom material laminated at the distal end thereof and a waterproofing peelable bottom material adapted for removal in order to deliver a drug to the skin or mucosa laminated to the skin. next surface of it. The figure provides a partially schematic sectional view of the transdermal drug delivery device (10) and includes the distant bottom layer (14) essentially impermeable to the drug, a drug-laden adhesive compound (18), and a liner (22). ) of near release essentially impermeable to the drug. The adhesive compound (18) comprises a layer (19) Distant adhesive, a close adhesive layer (20), and a layer (21) of gelled drug placed therebetween. The device is produced by extruding the drug in gel form towards at least one exposed surface of a first or second adhesive laminate, such that the adhesive layers and the gelled drug combine to form a composite adhesive layer containing drug that has Distant and proximal surfaces covered by respective background materials. This process is particularly suitable for the formulation of nicotine-containing parts.
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US20778694A | 1994-03-07 | 1994-03-07 | |
US207786 | 1994-03-07 | ||
US207,786 | 1994-03-07 | ||
PCT/US1995/000609 WO1995024172A1 (en) | 1994-03-07 | 1995-01-17 | Drug-containing adhesive composite transdermal delivery device |
Publications (2)
Publication Number | Publication Date |
---|---|
MXPA96003667A true MXPA96003667A (en) | 1997-06-01 |
MX9603667A MX9603667A (en) | 1997-06-28 |
Family
ID=22772001
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
MX9603667A MX9603667A (en) | 1994-03-07 | 1995-01-17 | Drug-containing adhesive composite transdermal delivery device. |
Country Status (14)
Country | Link |
---|---|
US (1) | US5626866A (en) |
EP (1) | EP0743842B1 (en) |
JP (1) | JP3021661B2 (en) |
KR (1) | KR100195873B1 (en) |
CN (1) | CN1131018C (en) |
AT (1) | ATE246909T1 (en) |
AU (1) | AU676430B2 (en) |
CA (1) | CA2183083C (en) |
DE (1) | DE69531488T2 (en) |
HK (1) | HK1010679A1 (en) |
MX (1) | MX9603667A (en) |
TW (1) | TW312624B (en) |
WO (1) | WO1995024172A1 (en) |
ZA (1) | ZA951427B (en) |
Families Citing this family (129)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5688523A (en) * | 1995-03-31 | 1997-11-18 | Minnesota Mining And Manufacturing Company | Method of making a pressure sensitive skin adhesive sheet material |
US6572879B1 (en) * | 1995-06-07 | 2003-06-03 | Alza Corporation | Formulations for transdermal delivery of pergolide |
DE19646392A1 (en) * | 1996-11-11 | 1998-05-14 | Lohmann Therapie Syst Lts | Preparation for use in the oral cavity with a layer containing pressure-sensitive adhesive, pharmaceuticals or cosmetics for dosed delivery |
US20060002959A1 (en) * | 1996-11-14 | 2006-01-05 | Government Of The United States | Skin-sctive adjuvants for transcutaneous immuization |
US6797276B1 (en) | 1996-11-14 | 2004-09-28 | The United States Of America As Represented By The Secretary Of The Army | Use of penetration enhancers and barrier disruption agents to enhance the transcutaneous immune response |
US20060002949A1 (en) * | 1996-11-14 | 2006-01-05 | Army Govt. Of The Usa, As Rep. By Secretary Of The Office Of The Command Judge Advocate, Hq Usamrmc. | Transcutaneous immunization without heterologous adjuvant |
US5980898A (en) * | 1996-11-14 | 1999-11-09 | The United States Of America As Represented By The U.S. Army Medical Research & Material Command | Adjuvant for transcutaneous immunization |
US6136297A (en) * | 1997-06-06 | 2000-10-24 | The Procter & Gamble Company | Delivery system for an oral care substance using a strip of material having low flexural stiffness |
US20020018754A1 (en) * | 1999-03-15 | 2002-02-14 | Paul Albert Sagel | Shapes for tooth whitening strips |
US6096328A (en) * | 1997-06-06 | 2000-08-01 | The Procter & Gamble Company | Delivery system for an oral care substance using a strip of material having low flexural stiffness |
US5989569A (en) * | 1997-06-06 | 1999-11-23 | The Procter & Gamble Company | Delivery system for a tooth whitener using a permanently deformable strip of material |
US5879691A (en) * | 1997-06-06 | 1999-03-09 | The Procter & Gamble Company | Delivery system for a tooth whitener using a strip of material having low flexural stiffness |
US6582708B1 (en) | 2000-06-28 | 2003-06-24 | The Procter & Gamble Company | Tooth whitening substance |
US5894017A (en) * | 1997-06-06 | 1999-04-13 | The Procter & Gamble Company | Delivery system for an oral care substance using a strip of material having low flexural stiffness |
US6045811A (en) * | 1997-06-06 | 2000-04-04 | The Procter & Gamble Company | Delivery system for an oral care substance using a permanently deformable strip of material |
US20040258703A1 (en) * | 1997-11-14 | 2004-12-23 | The Government Of The Us, As Represented By The Secretary Of The Army | Skin-active adjuvants for transcutaneous immunization |
US5965154A (en) * | 1998-03-17 | 1999-10-12 | Plc Holding, L.L.C. | Adhesive matrix type transdermal patch and method of manufacturing same |
US6974590B2 (en) | 1998-03-27 | 2005-12-13 | Cima Labs Inc. | Sublingual buccal effervescent |
US20030091629A1 (en) * | 1998-03-27 | 2003-05-15 | Cima Labs Inc. | Sublingual buccal effervescent |
US20030118645A1 (en) * | 1998-04-29 | 2003-06-26 | Pather S. Indiran | Pharmaceutical compositions for rectal and vaginal administration |
ES2226394T3 (en) * | 1998-05-22 | 2005-03-16 | Novosis Ag | TRANSDERMAL SYSTEMS CONTAINING ACTIVE SUBSTANCE THAT IS RELEASED CONTROLLED IN TIME. |
DE19826592A1 (en) | 1998-06-15 | 1999-12-16 | Lohmann Therapie Syst Lts | Process for producing a laminate consisting of individual layers |
JP2002531488A (en) * | 1998-12-07 | 2002-09-24 | エラン コーポレーシヨン ピーエルシー | Transdermal patches for delivering volatile liquid drugs |
CZ302035B6 (en) | 1998-12-18 | 2010-09-15 | Alza Corporation | Transparent transdermal nicotine delivery devices |
ATE529130T1 (en) * | 1999-04-08 | 2011-11-15 | Intercell Usa Inc | DRY FORMULATION FOR TRANSCUTANE IMMUNIZATION |
DE19918106A1 (en) * | 1999-04-22 | 2000-10-26 | Lohmann Therapie Syst Lts | Transdermal patches containing basic or neutral drug include adhesive (meth)acrylic acid polymer in alkali(ne earth) metal salt form |
HUP0201620A3 (en) | 1999-07-02 | 2003-02-28 | Procter & Gamble | Delivery system for oral care compositions comprising organosiloxane resins using a removable backing strip |
KR20010036685A (en) * | 1999-10-11 | 2001-05-07 | 김윤 | Transdermal fentanyl delivery matrix system |
US6322360B1 (en) * | 1999-10-22 | 2001-11-27 | 3M Innovative Properties Company | Medication retention assembly for oral delivery tray |
US8652446B2 (en) * | 2000-03-17 | 2014-02-18 | Lg Household & Healthcare Ltd. | Apparatus and method for whitening teeth |
KR100403699B1 (en) * | 2000-03-17 | 2003-11-01 | 주식회사 엘지생활건강 | Patches for teeth whitening |
US7785572B2 (en) | 2000-03-17 | 2010-08-31 | Lg Household And Health Care Ltd. | Method and device for teeth whitening using a dry type adhesive |
US6689344B2 (en) | 2000-03-17 | 2004-02-10 | Lg Household & Healthcare Ltd. | Patches for teeth whitening |
US6436428B1 (en) | 2000-03-21 | 2002-08-20 | Enhance Pharmaceuticals, Inc. | Device and method for treating urinary incontinence in females |
US7658942B2 (en) * | 2000-04-12 | 2010-02-09 | The Procter & Gamble Company | Cosmetic devices |
US7029694B2 (en) * | 2000-04-26 | 2006-04-18 | Watson Laboratories, Inc. | Compositions and methods for transdermal oxybutynin therapy |
US20030124177A1 (en) * | 2000-04-26 | 2003-07-03 | Watson Pharmaceuticals, Inc. | Compositions and methods for transdermal oxybutynin therapy |
WO2001080796A1 (en) * | 2000-04-26 | 2001-11-01 | Watson Pharmaceuticals, Inc. | Minimizing adverse experience associated with oxybutynin therapy |
US7179483B2 (en) * | 2000-04-26 | 2007-02-20 | Watson Pharmaceuticals, Inc. | Compositions and methods for transdermal oxybutynin therapy |
PL360092A1 (en) * | 2000-06-28 | 2004-09-06 | The Procter & Gamble Company | Structures and compositions increasing the stability of peroxide actives |
AU2002250071B2 (en) * | 2001-02-13 | 2008-02-14 | Government Of The United States, As Represented By The Secretary Of The Army | Vaccine for transcutaneous immunization |
DE10110391A1 (en) | 2001-03-03 | 2002-09-26 | Lohmann Therapie Syst Lts | Highly flexible nicotine transdermal therapeutic system with nicotine as active ingredient |
CA2445486A1 (en) * | 2001-03-19 | 2002-09-26 | Iomai Corporation | Patch for transcutaneous immunization |
US8268333B2 (en) * | 2001-04-24 | 2012-09-18 | Lintec Corporation | Orally administered agent and an orally administered agent/supporting substrate complex |
DE10121471A1 (en) * | 2001-05-02 | 2002-11-07 | Beiersdorf Ag | Plaster for controlled release of active agent to skin or wounds, comprising adsorbent, pressure-sensitive adhesive matrix surface-doped with active agent, e.g. dexpanthenol |
US6946142B2 (en) * | 2001-06-23 | 2005-09-20 | Lg Household & Healthcare Ltd. | Multi-layer patches for teeth whitening |
US20030068356A1 (en) * | 2001-07-10 | 2003-04-10 | Pather S. Indiran | Sequential drug delivery systems |
JP5089840B2 (en) * | 2001-09-25 | 2012-12-05 | 救急薬品工業株式会社 | Nicotine-containing film preparation |
US7273619B2 (en) * | 2002-01-17 | 2007-09-25 | Samyang Corporation | Transdermal composition of an antivomiting agent |
US20040033253A1 (en) * | 2002-02-19 | 2004-02-19 | Ihor Shevchuk | Acyl opioid antagonists |
EP1491185B1 (en) | 2002-03-14 | 2009-05-27 | Medrx Co., Ltd. | External medicine for wounds |
US20040137004A1 (en) * | 2002-03-19 | 2004-07-15 | Glenn Gregory M | Patch for transcutaneous immunization |
US20030194420A1 (en) * | 2002-04-11 | 2003-10-16 | Richard Holl | Process for loading a drug delivery device |
US6949240B2 (en) * | 2002-05-23 | 2005-09-27 | The Procter & Gamble Company | Tooth whitening products |
US8956160B2 (en) * | 2002-07-02 | 2015-02-17 | Ranir, Llc | Device and method for delivering an oral care agent |
GB0217056D0 (en) * | 2002-07-23 | 2002-08-28 | Ass Octel | Use |
GB0218996D0 (en) * | 2002-08-14 | 2002-09-25 | Novartis Ag | Organic compounds |
US8524200B2 (en) | 2002-09-11 | 2013-09-03 | The Procter & Gamble Company | Tooth whitening products |
US20050100515A1 (en) * | 2002-09-11 | 2005-05-12 | The Procter & Gamble Company | Tooth whitening products |
US20040120903A1 (en) * | 2002-09-11 | 2004-06-24 | The Procter & Gamble Company | Tooth whitening strips |
US6916463B2 (en) * | 2002-09-24 | 2005-07-12 | The Procter & Gamble Company | Oral products having an aesthetic layer |
WO2004075933A2 (en) * | 2003-02-26 | 2004-09-10 | Lavipharm S.A. | Devices for releasing volatile substances and methods of producing the devices |
AP2006003648A0 (en) * | 2003-12-05 | 2006-06-30 | Namibia Medical Invest Pty Ltd | Patch |
JP5244318B2 (en) * | 2003-12-31 | 2013-07-24 | シーマ・ラブス、インコーポレイテッド | Effervescent oral opiate dosage forms and methods of administration of opiates |
ME01300B (en) * | 2003-12-31 | 2013-12-20 | Cima Labs Inc | Generally linear effervescent oral fentanyl dosage form and methods of administering |
US7858121B2 (en) | 2003-12-31 | 2010-12-28 | Cima Labs, Inc. | Effervescent oral fentanyl dosage form and methods of administering fentanyl |
US20050202073A1 (en) * | 2004-03-09 | 2005-09-15 | Mylan Technologies, Inc. | Transdermal systems containing multilayer adhesive matrices to modify drug delivery |
AU2011203203B2 (en) * | 2004-03-09 | 2014-04-10 | Mylan Technologies, Inc | Transdermal systems containing multilayer adhesive matrices to modify drug delivery |
US9205062B2 (en) | 2004-03-09 | 2015-12-08 | Mylan Pharmaceuticals, Inc. | Transdermal systems containing multilayer adhesive matrices to modify drug delivery |
CN100455282C (en) * | 2004-03-17 | 2009-01-28 | 琳得科株式会社 | Process for producing medicine |
JP2005298471A (en) * | 2004-03-17 | 2005-10-27 | Lintec Corp | Method for producing medicine |
US20050220853A1 (en) * | 2004-04-02 | 2005-10-06 | Kinh-Luan Dao | Controlled delivery of therapeutic agents from medical articles |
WO2006023644A2 (en) * | 2004-08-20 | 2006-03-02 | 3M Innovative Properties Company | Transdermal drug delivery device with translucent protective film |
US8252320B2 (en) | 2004-10-21 | 2012-08-28 | Durect Corporation | Transdermal delivery system for sufentanil |
DK1814531T3 (en) | 2004-10-21 | 2010-10-11 | Durect Corp | Transdermal delivery systems |
US20060099550A1 (en) * | 2004-11-10 | 2006-05-11 | Ranir/Dcp Corporation | Device and method for delivering an oral care agent |
US20080138388A1 (en) * | 2005-02-04 | 2008-06-12 | Hisamitsu Pharmaceutical Co., Inc. | Transdermal Absorption Patch |
DE102005010255A1 (en) * | 2005-03-07 | 2006-09-14 | Lts Lohmann Therapie-Systeme Ag | Fiber-free transdermal therapeutic system and method for its production |
GB0508306D0 (en) * | 2005-04-25 | 2005-06-01 | Bioprogress Technology Ltd | Nicotine dosage forms |
JP5000932B2 (en) * | 2005-06-21 | 2012-08-15 | 日東電工株式会社 | Nicotine-containing transdermal preparation |
IL177071A0 (en) * | 2005-08-01 | 2006-12-10 | Nitto Denko Corp | Method of preparing a nicotine transdermal preparation |
US10137135B2 (en) | 2005-08-15 | 2018-11-27 | Allergan Sales, Llc | Formulations and methods for providing progestin-only contraception while minimizing adverse side effects associated therewith |
ES2499067T3 (en) | 2005-10-13 | 2014-09-26 | Nitto Denko Corporation | Transdermal preparation of nicotine and its production method |
JP2009516718A (en) * | 2005-11-23 | 2009-04-23 | ウニベルジテート チューリッヒ | Allergy treatment by transdermal allergen administration |
SE530184C2 (en) * | 2005-12-23 | 2008-03-18 | Kjell Stenberg | Bioadhesive pharmaceutical film composition containing low viscous alginates |
DE102006026060B4 (en) * | 2006-01-12 | 2013-01-31 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing as active ingredient nicotine and method for producing such systems |
US20070259029A1 (en) * | 2006-05-08 | 2007-11-08 | Mcentire Edward Enns | Water-dispersible patch containing an active agent for dermal delivery |
US20070258935A1 (en) * | 2006-05-08 | 2007-11-08 | Mcentire Edward Enns | Water dispersible films for delivery of active agents to the epidermis |
US20080057090A1 (en) * | 2006-09-01 | 2008-03-06 | Mcentire Edward Enns | Wrinkle masking film composition for skin |
US7879942B2 (en) * | 2006-10-05 | 2011-02-01 | Eastman Chemical Company | Switchable adhesive article for attachment to skin and method of using the same |
US20080175877A1 (en) * | 2007-01-22 | 2008-07-24 | Isense Corporation | Adhesives with antiperspirant and/or anti-inflammatory additives |
US20080287507A1 (en) * | 2007-05-16 | 2008-11-20 | John Hedenstrom | Nicotine containing toiletry waters |
JP2010528064A (en) * | 2007-05-31 | 2010-08-19 | フェルティン ファルマ アー/エス | Transdermal tobacco alkaloid reservoir patch |
US8246978B2 (en) * | 2007-07-10 | 2012-08-21 | Agile Therapeutics, Inc. | Dermal delivery device with reduced loss of its volatile components |
US8991402B2 (en) | 2007-12-18 | 2015-03-31 | Pax Labs, Inc. | Aerosol devices and methods for inhaling a substance and uses thereof |
EP2273002B1 (en) * | 2008-03-12 | 2016-04-27 | Shima Seiki Manufacturing., Ltd. | Knitted fabric designing system |
DE102008014533A1 (en) * | 2008-03-15 | 2009-09-17 | Lts Lohmann Therapie-Systeme Ag | Gingival wafer |
AU2010233833B2 (en) | 2009-03-31 | 2014-11-27 | Sanofi-Aventis Deutschland Gmbh | Method for manufacturing a drug delivery device body using an adhesive and drug delivery device body |
TWI552773B (en) * | 2009-05-01 | 2016-10-11 | 久光製藥股份有限公司 | Transdermal absorption preparation |
DE102010000661A1 (en) * | 2010-01-04 | 2011-07-07 | Acino Ag, 83714 | Method and device for producing an overlapping protective film for a transdermal therapeutic system |
EA023551B1 (en) * | 2010-07-29 | 2016-06-30 | Сантен Фармасьютикал Ко., Лтд. | Drug support body, and method for producing same |
US9301920B2 (en) | 2012-06-18 | 2016-04-05 | Therapeuticsmd, Inc. | Natural combination hormone replacement formulations and therapies |
JP6285866B2 (en) | 2011-11-23 | 2018-02-28 | セラピューティックスエムディー インコーポレーテッドTherapeuticsmd, Inc. | Natural complex hormone replacement preparations and therapies |
US9827146B2 (en) * | 2011-12-20 | 2017-11-28 | Sarasota Medical Products, Inc. | Manufacturing method for wound dressings |
US10806697B2 (en) | 2012-12-21 | 2020-10-20 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US20130338122A1 (en) | 2012-06-18 | 2013-12-19 | Therapeuticsmd, Inc. | Transdermal hormone replacement therapies |
US10806740B2 (en) | 2012-06-18 | 2020-10-20 | Therapeuticsmd, Inc. | Natural combination hormone replacement formulations and therapies |
US20150196640A1 (en) | 2012-06-18 | 2015-07-16 | Therapeuticsmd, Inc. | Progesterone formulations having a desirable pk profile |
EP2908798B1 (en) | 2012-10-17 | 2018-08-22 | The Procter and Gamble Company | Strip for the delivery of an oral care active and methods for applying oral care actives |
US9180091B2 (en) | 2012-12-21 | 2015-11-10 | Therapeuticsmd, Inc. | Soluble estradiol capsule for vaginal insertion |
US10471072B2 (en) | 2012-12-21 | 2019-11-12 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US10537581B2 (en) | 2012-12-21 | 2020-01-21 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US11246875B2 (en) | 2012-12-21 | 2022-02-15 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US10568891B2 (en) | 2012-12-21 | 2020-02-25 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US11266661B2 (en) | 2012-12-21 | 2022-03-08 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
CA3208137A1 (en) | 2013-05-06 | 2014-11-13 | Juul Labs, Inc. | Nicotine salt formulations for aerosol devices and methods thereof |
EP3076805A4 (en) | 2013-12-05 | 2017-10-11 | PAX Labs, Inc. | Nicotine liquid formulations for aerosol devices and methods thereof |
AU2015264003A1 (en) | 2014-05-22 | 2016-11-17 | Therapeuticsmd, Inc. | Natural combination hormone replacement formulations and therapies |
GB2535427A (en) | 2014-11-07 | 2016-08-24 | Nicoventures Holdings Ltd | Solution |
GB2532062A (en) | 2014-11-07 | 2016-05-11 | Nicoventures Holdings Ltd | Container |
US10328087B2 (en) | 2015-07-23 | 2019-06-25 | Therapeuticsmd, Inc. | Formulations for solubilizing hormones |
US10286077B2 (en) | 2016-04-01 | 2019-05-14 | Therapeuticsmd, Inc. | Steroid hormone compositions in medium chain oils |
BR112018070199A2 (en) | 2016-04-01 | 2019-01-29 | Therapeuticsmd Inc | pharmaceutical composition of steroid hormone |
CN106491569B (en) * | 2016-11-28 | 2019-10-01 | 南京工业大学 | A kind of smoking cessation hydrogel patch and preparation method thereof |
CN106512201A (en) * | 2017-01-14 | 2017-03-22 | 杨向鹏 | Pulmonary physical therapy solvent sustained-release device |
TWI795446B (en) * | 2017-10-04 | 2023-03-11 | 美商神經治療股份有限公司 | Dextromethorphan transdermal delivery device |
CN109498454B (en) * | 2019-01-14 | 2021-06-22 | 无锡市第二人民医院 | Operating method of small-batch production equipment for orthopedic plaster |
US11633405B2 (en) | 2020-02-07 | 2023-04-25 | Therapeuticsmd, Inc. | Steroid hormone pharmaceutical formulations |
DE102020112143B4 (en) | 2020-05-05 | 2022-03-17 | Lts Lohmann Therapie-Systeme Ag | Nicotine - Corona |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU426565B2 (en) * | 1971-06-17 | 1972-07-27 | Alza Corporation | Bandage for administering drugs |
US4597961A (en) * | 1985-01-23 | 1986-07-01 | Etscorn Frank T | Transcutaneous application of nicotine |
US5016652A (en) * | 1985-04-25 | 1991-05-21 | The Regents Of The University Of California | Method and apparatus for aiding in the reduction of incidence of tobacco smoking |
US4920989A (en) * | 1985-04-25 | 1990-05-01 | Regents Of The University Of California | Method and apparatus for aiding in the reduction of incidence of tobacco smoking |
US4715387A (en) * | 1985-08-23 | 1987-12-29 | The Regents Of The Univ. Of California | Aerosol for use in the reduction of tobacco smoking |
DE3727232A1 (en) * | 1987-08-14 | 1989-02-23 | Lohmann Therapie Syst Lts | METHOD FOR PRODUCING A PHARMACEUTICAL AND / OR DOSAGE FOR MEDICINAL ACTIVE SUBSTANCES |
US4943435A (en) * | 1987-10-05 | 1990-07-24 | Pharmetrix Corporation | Prolonged activity nicotine patch |
US4915950A (en) * | 1988-02-12 | 1990-04-10 | Cygnus Research Corporation | Printed transdermal drug delivery device |
GB8804164D0 (en) * | 1988-02-23 | 1988-03-23 | Tucker J M | Bandage for administering physiologically active compound |
US5077104A (en) * | 1989-12-21 | 1991-12-31 | Alza Corporation | Nicotine packaging materials |
-
1995
- 1995-01-17 WO PCT/US1995/000609 patent/WO1995024172A1/en active IP Right Grant
- 1995-01-17 KR KR1019960704599A patent/KR100195873B1/en not_active IP Right Cessation
- 1995-01-17 AU AU18318/95A patent/AU676430B2/en not_active Ceased
- 1995-01-17 EP EP95910095A patent/EP0743842B1/en not_active Expired - Lifetime
- 1995-01-17 JP JP7523436A patent/JP3021661B2/en not_active Expired - Fee Related
- 1995-01-17 DE DE69531488T patent/DE69531488T2/en not_active Expired - Lifetime
- 1995-01-17 CA CA002183083A patent/CA2183083C/en not_active Expired - Fee Related
- 1995-01-17 CN CN95191979A patent/CN1131018C/en not_active Expired - Fee Related
- 1995-01-17 MX MX9603667A patent/MX9603667A/en not_active IP Right Cessation
- 1995-01-17 AT AT95910095T patent/ATE246909T1/en not_active IP Right Cessation
- 1995-02-21 ZA ZA951427A patent/ZA951427B/en unknown
- 1995-03-06 TW TW084102126A patent/TW312624B/zh active
- 1995-10-17 US US08/544,110 patent/US5626866A/en not_active Expired - Lifetime
-
1998
- 1998-11-06 HK HK98111784A patent/HK1010679A1/en not_active IP Right Cessation
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA2183083C (en) | Drug-containing adhesive composite transdermal delivery device | |
MXPA96003667A (en) | Composed transdermal supply device adhesive containing dr | |
EP1225951B1 (en) | A dual adhesive transdermal drug delivery system | |
AU695170B2 (en) | Transdermal delivery system with adhesive overlay and peel seal disc | |
CA1276111C (en) | Transdermal verapamil delivery device | |
CA2064765C (en) | Biphasic transdermal drug delivery device | |
EP0848608B1 (en) | Supersaturated transdermal drug delivery systems, and methods for manufacturing the same | |
US5601839A (en) | Triacetin as a penetration enhancer for transdermal delivery of a basic drug | |
AU718096C (en) | Transdermal compositions containing low molecular weight drugs which are liquid at room temperatures | |
EP1637170A1 (en) | Transdermal compositions containing low molecular weight drugs which are liquid at room temperatures | |
CA2550704C (en) | Nicotine transdermal delivery system | |
AU4031289A (en) | Printed transdermal drug delivery device | |
WO1994004109A1 (en) | Printed transdermal drug delivery device | |
NZ234919A (en) | Polymeric matrix or reservoir transdermal nitroglycerin patch which contains n-methyl-2-pyrrolidone and/or penetration enhancer(s); preparatory processes | |
NZ240096A (en) | Fragrance releasing device |