NZ796300A - In vivo drug delivery devices and methods for drug delivery - Google Patents
In vivo drug delivery devices and methods for drug deliveryInfo
- Publication number
- NZ796300A NZ796300A NZ796300A NZ79630018A NZ796300A NZ 796300 A NZ796300 A NZ 796300A NZ 796300 A NZ796300 A NZ 796300A NZ 79630018 A NZ79630018 A NZ 79630018A NZ 796300 A NZ796300 A NZ 796300A
- Authority
- NZ
- New Zealand
- Prior art keywords
- drug
- release
- restraining
- reservoir
- plug
- Prior art date
Links
- 238000012377 drug delivery Methods 0.000 title claims abstract description 119
- 238000000034 method Methods 0.000 title abstract description 43
- 238000001727 in vivo Methods 0.000 title description 7
- 239000003814 drug Substances 0.000 claims abstract description 364
- 206010046543 Urinary incontinence Diseases 0.000 claims abstract description 8
- 210000003932 urinary bladder Anatomy 0.000 claims description 72
- 229960001491 trospium Drugs 0.000 claims description 54
- OYYDSUSKLWTMMQ-JKHIJQBDSA-N trospium Chemical compound [N+]12([C@@H]3CC[C@H]2C[C@H](C3)OC(=O)C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CCCC1 OYYDSUSKLWTMMQ-JKHIJQBDSA-N 0.000 claims description 54
- 238000011282 treatment Methods 0.000 claims description 39
- 210000002700 urine Anatomy 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 229940079593 drug Drugs 0.000 abstract description 360
- 230000000452 restraining effect Effects 0.000 abstract description 195
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 41
- 229910001868 water Inorganic materials 0.000 abstract description 30
- 230000001052 transient effect Effects 0.000 abstract description 13
- 208000020431 spinal cord injury Diseases 0.000 abstract description 10
- 230000001272 neurogenic effect Effects 0.000 abstract description 7
- 206010037211 Psychomotor hyperactivity Diseases 0.000 abstract description 6
- 206010020853 Hypertonic bladder Diseases 0.000 abstract description 5
- 208000009722 Overactive Urinary Bladder Diseases 0.000 abstract description 5
- 208000020629 overactive bladder Diseases 0.000 abstract description 5
- 230000014759 maintenance of location Effects 0.000 description 68
- 239000000463 material Substances 0.000 description 46
- 239000013583 drug formulation Substances 0.000 description 41
- 229920001296 polysiloxane Polymers 0.000 description 31
- 230000002706 hydrostatic effect Effects 0.000 description 26
- -1 diamorphone Chemical compound 0.000 description 20
- RVCSYOQWLPPAOA-CVPHZBIISA-M [(5s)-spiro[8-azoniabicyclo[3.2.1]octane-8,1'-azolidin-1-ium]-3-yl] 2-hydroxy-2,2-diphenylacetate;chloride Chemical compound [Cl-].[N+]12([C@H]3CCC2CC(C3)OC(=O)C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CCCC1 RVCSYOQWLPPAOA-CVPHZBIISA-M 0.000 description 18
- 230000015572 biosynthetic process Effects 0.000 description 18
- 230000003204 osmotic effect Effects 0.000 description 18
- 229960001530 trospium chloride Drugs 0.000 description 18
- 239000000853 adhesive Substances 0.000 description 16
- 230000001070 adhesive effect Effects 0.000 description 16
- 150000002500 ions Chemical class 0.000 description 16
- 239000003826 tablet Substances 0.000 description 15
- 230000001186 cumulative effect Effects 0.000 description 14
- 125000006850 spacer group Chemical group 0.000 description 14
- 238000000338 in vitro Methods 0.000 description 13
- 239000007787 solid Substances 0.000 description 13
- 238000002474 experimental method Methods 0.000 description 12
- 238000003780 insertion Methods 0.000 description 12
- 230000037431 insertion Effects 0.000 description 12
- 230000008859 change Effects 0.000 description 11
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 10
- 239000012530 fluid Substances 0.000 description 10
- 239000002357 osmotic agent Substances 0.000 description 10
- 239000003795 chemical substances by application Substances 0.000 description 9
- 238000004891 communication Methods 0.000 description 9
- 230000007246 mechanism Effects 0.000 description 9
- 238000013461 design Methods 0.000 description 8
- 238000011049 filling Methods 0.000 description 8
- 210000001519 tissue Anatomy 0.000 description 8
- 238000000576 coating method Methods 0.000 description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
- 239000003193 general anesthetic agent Substances 0.000 description 7
- 238000005192 partition Methods 0.000 description 7
- 239000013464 silicone adhesive Substances 0.000 description 7
- 210000003708 urethra Anatomy 0.000 description 7
- 239000000560 biocompatible material Substances 0.000 description 6
- 239000008367 deionised water Substances 0.000 description 6
- 229910021641 deionized water Inorganic materials 0.000 description 6
- 230000004941 influx Effects 0.000 description 6
- 230000027939 micturition Effects 0.000 description 6
- 239000003149 muscarinic antagonist Substances 0.000 description 6
- 235000012434 pretzels Nutrition 0.000 description 6
- XIQVNETUBQGFHX-UHFFFAOYSA-N Ditropan Chemical compound C=1C=CC=CC=1C(O)(C(=O)OCC#CCN(CC)CC)C1CCCCC1 XIQVNETUBQGFHX-UHFFFAOYSA-N 0.000 description 5
- 206010021639 Incontinence Diseases 0.000 description 5
- 239000011248 coating agent Substances 0.000 description 5
- 230000007423 decrease Effects 0.000 description 5
- 238000009792 diffusion process Methods 0.000 description 5
- 229960004679 doxorubicin Drugs 0.000 description 5
- 229960005434 oxybutynin Drugs 0.000 description 5
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 5
- 238000007789 sealing Methods 0.000 description 5
- VRBFTYUMFJWSJY-UHFFFAOYSA-N 28804-46-8 Chemical compound ClC1CC(C=C2)=CC=C2C(Cl)CC2=CC=C1C=C2 VRBFTYUMFJWSJY-UHFFFAOYSA-N 0.000 description 4
- 108091006146 Channels Proteins 0.000 description 4
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 4
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 4
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 4
- 208000002193 Pain Diseases 0.000 description 4
- 229960000190 bacillus calmette–guérin vaccine Drugs 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 230000006870 function Effects 0.000 description 4
- 208000015181 infectious disease Diseases 0.000 description 4
- 229960004194 lidocaine Drugs 0.000 description 4
- HLXZNVUGXRDIFK-UHFFFAOYSA-N nickel titanium Chemical compound [Ti].[Ti].[Ti].[Ti].[Ti].[Ti].[Ti].[Ti].[Ti].[Ti].[Ti].[Ni].[Ni].[Ni].[Ni].[Ni].[Ni].[Ni].[Ni].[Ni].[Ni].[Ni].[Ni].[Ni].[Ni] HLXZNVUGXRDIFK-UHFFFAOYSA-N 0.000 description 4
- 229910001000 nickel titanium Inorganic materials 0.000 description 4
- 230000035699 permeability Effects 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 229920000052 poly(p-xylylene) Polymers 0.000 description 4
- 229920000642 polymer Polymers 0.000 description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 4
- 230000004044 response Effects 0.000 description 4
- 239000005720 sucrose Substances 0.000 description 4
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 208000005615 Interstitial Cystitis Diseases 0.000 description 3
- 241001467552 Mycobacterium bovis BCG Species 0.000 description 3
- QPCVHQBVMYCJOM-UHFFFAOYSA-N Propiverine Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(OCCC)C(=O)OC1CCN(C)CC1 QPCVHQBVMYCJOM-UHFFFAOYSA-N 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 239000000556 agonist Substances 0.000 description 3
- 230000003444 anaesthetic effect Effects 0.000 description 3
- 230000001022 anti-muscarinic effect Effects 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 210000001124 body fluid Anatomy 0.000 description 3
- 239000000812 cholinergic antagonist Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- ZPUCINDJVBIVPJ-LJISPDSOSA-N cocaine Chemical class O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-LJISPDSOSA-N 0.000 description 3
- 238000013267 controlled drug release Methods 0.000 description 3
- 238000013270 controlled release Methods 0.000 description 3
- 229940127089 cytotoxic agent Drugs 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 229960001904 epirubicin Drugs 0.000 description 3
- 239000005038 ethylene vinyl acetate Substances 0.000 description 3
- 229960000855 flavoxate Drugs 0.000 description 3
- SPIUTQOUKAMGCX-UHFFFAOYSA-N flavoxate Chemical compound C1=CC=C2C(=O)C(C)=C(C=3C=CC=CC=3)OC2=C1C(=O)OCCN1CCCCC1 SPIUTQOUKAMGCX-UHFFFAOYSA-N 0.000 description 3
- 229960005277 gemcitabine Drugs 0.000 description 3
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 3
- 238000002513 implantation Methods 0.000 description 3
- 238000007925 in vitro drug release testing Methods 0.000 description 3
- 230000006698 induction Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 239000008185 minitablet Substances 0.000 description 3
- 229960004857 mitomycin Drugs 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 229960003510 propiverine Drugs 0.000 description 3
- 239000000333 selective estrogen receptor modulator Substances 0.000 description 3
- 229940095743 selective estrogen receptor modulator Drugs 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 229960000653 valrubicin Drugs 0.000 description 3
- ZOCKGBMQLCSHFP-KQRAQHLDSA-N valrubicin Chemical compound O([C@H]1C[C@](CC2=C(O)C=3C(=O)C4=CC=CC(OC)=C4C(=O)C=3C(O)=C21)(O)C(=O)COC(=O)CCCC)[C@H]1C[C@H](NC(=O)C(F)(F)F)[C@H](O)[C@H](C)O1 ZOCKGBMQLCSHFP-KQRAQHLDSA-N 0.000 description 3
- 239000011800 void material Substances 0.000 description 3
- ZKMNUMMKYBVTFN-HNNXBMFYSA-N (S)-ropivacaine Chemical compound CCCN1CCCC[C@H]1C(=O)NC1=C(C)C=CC=C1C ZKMNUMMKYBVTFN-HNNXBMFYSA-N 0.000 description 2
- LEBVLXFERQHONN-UHFFFAOYSA-N 1-butyl-N-(2,6-dimethylphenyl)piperidine-2-carboxamide Chemical compound CCCCN1CCCCC1C(=O)NC1=C(C)C=CC=C1C LEBVLXFERQHONN-UHFFFAOYSA-N 0.000 description 2
- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 description 2
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical compound O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 2
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 2
- MXPOCMVWFLDDLZ-NSCUHMNNSA-N Apaziquone Chemical compound CN1C(\C=C\CO)=C(CO)C(C2=O)=C1C(=O)C=C2N1CC1 MXPOCMVWFLDDLZ-NSCUHMNNSA-N 0.000 description 2
- 229930003347 Atropine Natural products 0.000 description 2
- 206010005003 Bladder cancer Diseases 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 description 2
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 2
- IKYCZSUNGFRBJS-UHFFFAOYSA-N Euphorbia factor RL9 = U(1) = Resiniferatoxin Natural products COC1=CC(O)=CC(CC(=O)OCC=2CC3(O)C(=O)C(C)=CC3C34C(C)CC5(OC(O4)(CC=4C=CC=CC=4)OC5C3C=2)C(C)=C)=C1 IKYCZSUNGFRBJS-UHFFFAOYSA-N 0.000 description 2
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 2
- 239000005715 Fructose Substances 0.000 description 2
- RKUNBYITZUJHSG-UHFFFAOYSA-N Hyosciamin-hydrochlorid Natural products CN1C(C2)CCC1CC2OC(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-UHFFFAOYSA-N 0.000 description 2
- 208000000913 Kidney Calculi Diseases 0.000 description 2
- 102000043136 MAP kinase family Human genes 0.000 description 2
- 108091054455 MAP kinase family Proteins 0.000 description 2
- 229930192392 Mitomycin Natural products 0.000 description 2
- DEXMFYZAHXMZNM-UHFFFAOYSA-N Narceine Chemical compound OC(=O)C1=C(OC)C(OC)=CC=C1C(=O)CC1=C(CCN(C)C)C=C(OCO2)C2=C1OC DEXMFYZAHXMZNM-UHFFFAOYSA-N 0.000 description 2
- 206010029148 Nephrolithiasis Diseases 0.000 description 2
- 208000000693 Neurogenic Urinary Bladder Diseases 0.000 description 2
- 206010029279 Neurogenic bladder Diseases 0.000 description 2
- 206010033372 Pain and discomfort Diseases 0.000 description 2
- 208000004550 Postoperative Pain Diseases 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- VVWYOYDLCMFIEM-UHFFFAOYSA-N Propantheline Chemical compound C1=CC=C2C(C(=O)OCC[N+](C)(C(C)C)C(C)C)C3=CC=CC=C3OC2=C1 VVWYOYDLCMFIEM-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 210000001744 T-lymphocyte Anatomy 0.000 description 2
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 2
- 239000004433 Thermoplastic polyurethane Substances 0.000 description 2
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 208000000921 Urge Urinary Incontinence Diseases 0.000 description 2
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 2
- 208000006593 Urologic Neoplasms Diseases 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 229910045601 alloy Inorganic materials 0.000 description 2
- 239000000956 alloy Substances 0.000 description 2
- 239000002160 alpha blocker Substances 0.000 description 2
- 229960000836 amitriptyline Drugs 0.000 description 2
- KRMDCWKBEZIMAB-UHFFFAOYSA-N amitriptyline Chemical compound C1CC2=CC=CC=C2C(=CCCN(C)C)C2=CC=CC=C21 KRMDCWKBEZIMAB-UHFFFAOYSA-N 0.000 description 2
- 229940035674 anesthetics Drugs 0.000 description 2
- 239000000730 antalgic agent Substances 0.000 description 2
- 229940125681 anticonvulsant agent Drugs 0.000 description 2
- 239000001961 anticonvulsive agent Substances 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 229940124575 antispasmodic agent Drugs 0.000 description 2
- 229950002465 apaziquone Drugs 0.000 description 2
- RKUNBYITZUJHSG-SPUOUPEWSA-N atropine Chemical compound O([C@H]1C[C@H]2CC[C@@H](C1)N2C)C(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-SPUOUPEWSA-N 0.000 description 2
- 229960000396 atropine Drugs 0.000 description 2
- BLFLLBZGZJTVJG-UHFFFAOYSA-N benzocaine Chemical compound CCOC(=O)C1=CC=C(N)C=C1 BLFLLBZGZJTVJG-UHFFFAOYSA-N 0.000 description 2
- 229960003150 bupivacaine Drugs 0.000 description 2
- DQXBYHZEEUGOBF-UHFFFAOYSA-N but-3-enoic acid;ethene Chemical compound C=C.OC(=O)CC=C DQXBYHZEEUGOBF-UHFFFAOYSA-N 0.000 description 2
- YKPUWZUDDOIDPM-SOFGYWHQSA-N capsaicin Chemical compound COC1=CC(CNC(=O)CCCC\C=C\C(C)C)=CC=C1O YKPUWZUDDOIDPM-SOFGYWHQSA-N 0.000 description 2
- 235000017663 capsaicin Nutrition 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 230000001713 cholinergic effect Effects 0.000 description 2
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 2
- 238000007906 compression Methods 0.000 description 2
- 230000006835 compression Effects 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 238000010276 construction Methods 0.000 description 2
- 230000008602 contraction Effects 0.000 description 2
- 239000008121 dextrose Substances 0.000 description 2
- XYYVYLMBEZUESM-UHFFFAOYSA-N dihydrocodeine Natural products C1C(N(CCC234)C)C2C=CC(=O)C3OC2=C4C1=CC=C2OC XYYVYLMBEZUESM-UHFFFAOYSA-N 0.000 description 2
- 229950010160 dimethocaine Drugs 0.000 description 2
- OWQIUQKMMPDHQQ-UHFFFAOYSA-N dimethocaine Chemical compound CCN(CC)CC(C)(C)COC(=O)C1=CC=C(N)C=C1 OWQIUQKMMPDHQQ-UHFFFAOYSA-N 0.000 description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 230000009977 dual effect Effects 0.000 description 2
- 239000013013 elastic material Substances 0.000 description 2
- 239000013536 elastomeric material Substances 0.000 description 2
- 230000004761 fibrosis Effects 0.000 description 2
- 229960002949 fluorouracil Drugs 0.000 description 2
- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 description 2
- BCGWQEUPMDMJNV-UHFFFAOYSA-N imipramine Chemical compound C1CC2=CC=CC=C2N(CCCN(C)C)C2=CC=CC=C21 BCGWQEUPMDMJNV-UHFFFAOYSA-N 0.000 description 2
- 229960004801 imipramine Drugs 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 238000011068 loading method Methods 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 229920002521 macromolecule Polymers 0.000 description 2
- 210000002540 macrophage Anatomy 0.000 description 2
- 238000007726 management method Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000003158 myorelaxant agent Substances 0.000 description 2
- 229960003820 pentosan polysulfate sodium Drugs 0.000 description 2
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229960004919 procaine Drugs 0.000 description 2
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 2
- 229960000697 propantheline Drugs 0.000 description 2
- 229960003981 proparacaine Drugs 0.000 description 2
- 201000007608 radiation cystitis Diseases 0.000 description 2
- DSDNAKHZNJAGHN-UHFFFAOYSA-N resinferatoxin Natural products C1=C(O)C(OC)=CC(CC(=O)OCC=2CC3(O)C(=O)C(C)=CC3C34C(C)CC5(OC(O4)(CC=4C=CC=CC=4)OC5C3C=2)C(C)=C)=C1 DSDNAKHZNJAGHN-UHFFFAOYSA-N 0.000 description 2
- DSDNAKHZNJAGHN-MXTYGGKSSA-N resiniferatoxin Chemical compound C1=C(O)C(OC)=CC(CC(=O)OCC=2C[C@]3(O)C(=O)C(C)=C[C@H]3[C@@]34[C@H](C)C[C@@]5(O[C@@](O4)(CC=4C=CC=CC=4)O[C@@H]5[C@@H]3C=2)C(C)=C)=C1 DSDNAKHZNJAGHN-MXTYGGKSSA-N 0.000 description 2
- 229940073454 resiniferatoxin Drugs 0.000 description 2
- 230000000717 retained effect Effects 0.000 description 2
- NBFQYHKHPBMJJV-UHFFFAOYSA-N risocaine Chemical compound CCCOC(=O)C1=CC=C(N)C=C1 NBFQYHKHPBMJJV-UHFFFAOYSA-N 0.000 description 2
- 229960001549 ropivacaine Drugs 0.000 description 2
- 150000003839 salts Chemical group 0.000 description 2
- QUCDWLYKDRVKMI-UHFFFAOYSA-M sodium;3,4-dimethylbenzenesulfonate Chemical compound [Na+].CC1=CC=C(S([O-])(=O)=O)C=C1C QUCDWLYKDRVKMI-UHFFFAOYSA-M 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 229920002803 thermoplastic polyurethane Polymers 0.000 description 2
- 229960001196 thiotepa Drugs 0.000 description 2
- 229960004045 tolterodine Drugs 0.000 description 2
- OOGJQPCLVADCPB-HXUWFJFHSA-N tolterodine Chemical compound C1([C@@H](CCN(C(C)C)C(C)C)C=2C(=CC=C(C)C=2)O)=CC=CC=C1 OOGJQPCLVADCPB-HXUWFJFHSA-N 0.000 description 2
- 201000005112 urinary bladder cancer Diseases 0.000 description 2
- 230000002485 urinary effect Effects 0.000 description 2
- BDIAUFOIMFAIPU-UHFFFAOYSA-N valepotriate Natural products CC(C)CC(=O)OC1C=C(C(=COC2OC(=O)CC(C)C)COC(C)=O)C2C11CO1 BDIAUFOIMFAIPU-UHFFFAOYSA-N 0.000 description 2
- 229960001722 verapamil Drugs 0.000 description 2
- KQODQNJLJQHFQV-UHFFFAOYSA-N (-)-hemiasterlin Natural products C1=CC=C2C(C(C)(C)C(C(=O)NC(C(=O)N(C)C(C=C(C)C(O)=O)C(C)C)C(C)(C)C)NC)=CN(C)C2=C1 KQODQNJLJQHFQV-UHFFFAOYSA-N 0.000 description 1
- UVITTYOJFDLOGI-UHFFFAOYSA-N (1,2,5-trimethyl-4-phenylpiperidin-4-yl) propanoate Chemical compound C=1C=CC=CC=1C1(OC(=O)CC)CC(C)N(C)CC1C UVITTYOJFDLOGI-UHFFFAOYSA-N 0.000 description 1
- RJMIEHBSYVWVIN-LLVKDONJSA-N (2r)-2-[4-(3-oxo-1h-isoindol-2-yl)phenyl]propanoic acid Chemical compound C1=CC([C@H](C(O)=O)C)=CC=C1N1C(=O)C2=CC=CC=C2C1 RJMIEHBSYVWVIN-LLVKDONJSA-N 0.000 description 1
- GRYSXUXXBDSYRT-WOUKDFQISA-N (2r,3r,4r,5r)-2-(hydroxymethyl)-4-methoxy-5-[6-(methylamino)purin-9-yl]oxolan-3-ol Chemical compound C1=NC=2C(NC)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1OC GRYSXUXXBDSYRT-WOUKDFQISA-N 0.000 description 1
- PJVXUVWGSCCGHT-ZPYZYFCMSA-N (2r,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanal;(3s,4r,5r)-1,3,4,5,6-pentahydroxyhexan-2-one Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O.OC[C@@H](O)[C@@H](O)[C@H](O)C(=O)CO PJVXUVWGSCCGHT-ZPYZYFCMSA-N 0.000 description 1
- BWNLUIXQIHPUGO-RDTXWAMCSA-N (2r,4r)-4-(dimethylamino)-2-phenyl-2-pyridin-2-ylpentanamide Chemical compound C1([C@](C(N)=O)(C[C@@H](C)N(C)C)C=2N=CC=CC=2)=CC=CC=C1 BWNLUIXQIHPUGO-RDTXWAMCSA-N 0.000 description 1
- WRRSFOZOETZUPG-FFHNEAJVSA-N (4r,4ar,7s,7ar,12bs)-9-methoxy-3-methyl-2,4,4a,7,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-ol;hydrate Chemical compound O.C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC WRRSFOZOETZUPG-FFHNEAJVSA-N 0.000 description 1
- SGKRLCUYIXIAHR-AKNGSSGZSA-N (4s,4ar,5s,5ar,6r,12ar)-4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1=CC=C2[C@H](C)[C@@H]([C@H](O)[C@@H]3[C@](C(O)=C(C(N)=O)C(=O)[C@H]3N(C)C)(O)C3=O)C3=C(O)C2=C1O SGKRLCUYIXIAHR-AKNGSSGZSA-N 0.000 description 1
- TVYLLZQTGLZFBW-ZBFHGGJFSA-N (R,R)-tramadol Chemical compound COC1=CC=CC([C@]2(O)[C@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-ZBFHGGJFSA-N 0.000 description 1
- MWHXMIASLKXGBU-RNCYCKTQSA-N (e)-but-2-enedioic acid;[2-[(1r)-3-[di(propan-2-yl)amino]-1-phenylpropyl]-4-(hydroxymethyl)phenyl] 2-methylpropanoate Chemical compound OC(=O)\C=C\C(O)=O.C1([C@@H](CCN(C(C)C)C(C)C)C=2C(=CC=C(CO)C=2)OC(=O)C(C)C)=CC=CC=C1 MWHXMIASLKXGBU-RNCYCKTQSA-N 0.000 description 1
- KQODQNJLJQHFQV-MKWZWQCGSA-N (e,4s)-4-[[(2s)-3,3-dimethyl-2-[[(2s)-3-methyl-2-(methylamino)-3-(1-methylindol-3-yl)butanoyl]amino]butanoyl]-methylamino]-2,5-dimethylhex-2-enoic acid Chemical compound C1=CC=C2C(C(C)(C)[C@@H](C(=O)N[C@H](C(=O)N(C)[C@H](\C=C(/C)C(O)=O)C(C)C)C(C)(C)C)NC)=CN(C)C2=C1 KQODQNJLJQHFQV-MKWZWQCGSA-N 0.000 description 1
- CNTMOLDWXSVYKD-PSRNMDMQSA-N (e,4s)-4-[[(2s)-3,3-dimethyl-2-[[(2s)-3-methyl-2-(methylamino)-3-phenylbutanoyl]amino]butanoyl]-methylamino]-2,5-dimethylhex-2-enoic acid Chemical compound OC(=O)C(/C)=C/[C@H](C(C)C)N(C)C(=O)[C@H](C(C)(C)C)NC(=O)[C@@H](NC)C(C)(C)C1=CC=CC=C1 CNTMOLDWXSVYKD-PSRNMDMQSA-N 0.000 description 1
- BFUUJUGQJUTPAF-UHFFFAOYSA-N 2-(3-amino-4-propoxybenzoyl)oxyethyl-diethylazanium;chloride Chemical compound [Cl-].CCCOC1=CC=C(C(=O)OCC[NH+](CC)CC)C=C1N BFUUJUGQJUTPAF-UHFFFAOYSA-N 0.000 description 1
- JMLXKDZVBYFSBK-UHFFFAOYSA-N 2-(hexylamino)-4-oxopentanoic acid Chemical compound CCCCCCNC(C(O)=O)CC(C)=O JMLXKDZVBYFSBK-UHFFFAOYSA-N 0.000 description 1
- XKSAJZSJKURQRX-UHFFFAOYSA-N 2-acetyloxy-5-(4-fluorophenyl)benzoic acid Chemical compound C1=C(C(O)=O)C(OC(=O)C)=CC=C1C1=CC=C(F)C=C1 XKSAJZSJKURQRX-UHFFFAOYSA-N 0.000 description 1
- UJABSZITRMATFL-UHFFFAOYSA-N 2-methyl-5-phenylfuran-3-carbonyl chloride Chemical compound ClC(=O)C1=C(C)OC(C=2C=CC=CC=2)=C1 UJABSZITRMATFL-UHFFFAOYSA-N 0.000 description 1
- IYNWSQDZXMGGGI-NUEKZKHPSA-N 3-hydroxymorphinan Chemical compound C1CCC[C@H]2[C@H]3CC4=CC=C(O)C=C4[C@]21CCN3 IYNWSQDZXMGGGI-NUEKZKHPSA-N 0.000 description 1
- WZRJTRPJURQBRM-UHFFFAOYSA-N 4-amino-n-(5-methyl-1,2-oxazol-3-yl)benzenesulfonamide;5-[(3,4,5-trimethoxyphenyl)methyl]pyrimidine-2,4-diamine Chemical compound O1C(C)=CC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1.COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 WZRJTRPJURQBRM-UHFFFAOYSA-N 0.000 description 1
- HQFWVSGBVLEQGA-UHFFFAOYSA-N 4-aminobenzoic acid 3-(dibutylamino)propyl ester Chemical compound CCCCN(CCCC)CCCOC(=O)C1=CC=C(N)C=C1 HQFWVSGBVLEQGA-UHFFFAOYSA-N 0.000 description 1
- SQDAZGGFXASXDW-UHFFFAOYSA-N 5-bromo-2-(trifluoromethoxy)pyridine Chemical compound FC(F)(F)OC1=CC=C(Br)C=N1 SQDAZGGFXASXDW-UHFFFAOYSA-N 0.000 description 1
- BSYNRYMUTXBXSQ-FOQJRBATSA-N 59096-14-9 Chemical compound CC(=O)OC1=CC=CC=C1[14C](O)=O BSYNRYMUTXBXSQ-FOQJRBATSA-N 0.000 description 1
- USSIQXCVUWKGNF-UHFFFAOYSA-N 6-(dimethylamino)-4,4-diphenylheptan-3-one Chemical compound C=1C=CC=CC=1C(CC(C)N(C)C)(C(=O)CC)C1=CC=CC=C1 USSIQXCVUWKGNF-UHFFFAOYSA-N 0.000 description 1
- SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 description 1
- ZGXJTSGNIOSYLO-UHFFFAOYSA-N 88755TAZ87 Chemical compound NCC(=O)CCC(O)=O ZGXJTSGNIOSYLO-UHFFFAOYSA-N 0.000 description 1
- GSDSWSVVBLHKDQ-UHFFFAOYSA-N 9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid Chemical compound FC1=CC(C(C(C(O)=O)=C2)=O)=C3N2C(C)COC3=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-UHFFFAOYSA-N 0.000 description 1
- 229930000680 A04AD01 - Scopolamine Natural products 0.000 description 1
- QTGIAADRBBLJGA-UHFFFAOYSA-N Articaine Chemical compound CCCNC(C)C(=O)NC=1C(C)=CSC=1C(=O)OC QTGIAADRBBLJGA-UHFFFAOYSA-N 0.000 description 1
- KPYSYYIEGFHWSV-UHFFFAOYSA-N Baclofen Chemical compound OC(=O)CC(CN)C1=CC=C(Cl)C=C1 KPYSYYIEGFHWSV-UHFFFAOYSA-N 0.000 description 1
- 208000031872 Body Remains Diseases 0.000 description 1
- 108030001720 Bontoxilysin Proteins 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 108090000312 Calcium Channels Proteins 0.000 description 1
- 102000003922 Calcium Channels Human genes 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- 102100025064 Cellular tumor antigen p53 Human genes 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 229920001287 Chondroitin sulfate Polymers 0.000 description 1
- 241000070918 Cima Species 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- 206010011793 Cystitis haemorrhagic Diseases 0.000 description 1
- 108010000437 Deamino Arginine Vasopressin Proteins 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- IJVCSMSMFSCRME-KBQPJGBKSA-N Dihydromorphine Chemical compound O([C@H]1[C@H](CC[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O IJVCSMSMFSCRME-KBQPJGBKSA-N 0.000 description 1
- 208000010228 Erectile Dysfunction Diseases 0.000 description 1
- OGDVEMNWJVYAJL-LEPYJNQMSA-N Ethyl morphine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OCC OGDVEMNWJVYAJL-LEPYJNQMSA-N 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- OGDVEMNWJVYAJL-UHFFFAOYSA-N Ethylmorphine Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OCC OGDVEMNWJVYAJL-UHFFFAOYSA-N 0.000 description 1
- VTUSIVBDOCDNHS-UHFFFAOYSA-N Etidocaine Chemical compound CCCN(CC)C(CC)C(=O)NC1=C(C)C=CC=C1C VTUSIVBDOCDNHS-UHFFFAOYSA-N 0.000 description 1
- 108050007372 Fibroblast Growth Factor Proteins 0.000 description 1
- 102000018233 Fibroblast Growth Factor Human genes 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- NMJREATYWWNIKX-UHFFFAOYSA-N GnRH Chemical compound C1CCC(C(=O)NCC(N)=O)N1C(=O)C(CC(C)C)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)CNC(=O)C(NC(=O)C(CO)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C(CC=1NC=NC=1)NC(=O)C1NC(=O)CC1)CC1=CC=C(O)C=C1 NMJREATYWWNIKX-UHFFFAOYSA-N 0.000 description 1
- 108010072471 HTI-286 Proteins 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- GVGLGOZIDCSQPN-PVHGPHFFSA-N Heroin Chemical compound O([C@H]1[C@H](C=C[C@H]23)OC(C)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4OC(C)=O GVGLGOZIDCSQPN-PVHGPHFFSA-N 0.000 description 1
- DKLKMKYDWHYZTD-UHFFFAOYSA-N Hexylcaine Chemical compound C=1C=CC=CC=1C(=O)OC(C)CNC1CCCCC1 DKLKMKYDWHYZTD-UHFFFAOYSA-N 0.000 description 1
- 101000721661 Homo sapiens Cellular tumor antigen p53 Proteins 0.000 description 1
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical class NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 1
- STECJAGHUSJQJN-GAUPFVANSA-N Hyoscine Natural products C1([C@H](CO)C(=O)OC2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-GAUPFVANSA-N 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 1
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- VDJHFHXMUKFKET-UHFFFAOYSA-N Ingenol mebutate Natural products CC1CC2C(C)(C)C2C2C=C(CO)C(O)C3(O)C(OC(=O)C(C)=CC)C(C)=CC31C2=O VDJHFHXMUKFKET-UHFFFAOYSA-N 0.000 description 1
- 102100037850 Interferon gamma Human genes 0.000 description 1
- 108010074328 Interferon-gamma Proteins 0.000 description 1
- 108010002350 Interleukin-2 Proteins 0.000 description 1
- ALFGKMXHOUSVAD-UHFFFAOYSA-N Ketobemidone Chemical compound C=1C=CC(O)=CC=1C1(C(=O)CC)CCN(C)CC1 ALFGKMXHOUSVAD-UHFFFAOYSA-N 0.000 description 1
- 206010023421 Kidney fibrosis Diseases 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 1
- 102000004407 Lactalbumin Human genes 0.000 description 1
- 108090000942 Lactalbumin Proteins 0.000 description 1
- JAQUASYNZVUNQP-USXIJHARSA-N Levorphanol Chemical compound C1C2=CC=C(O)C=C2[C@]23CCN(C)[C@H]1[C@@H]2CCCC3 JAQUASYNZVUNQP-USXIJHARSA-N 0.000 description 1
- XADCESSVHJOZHK-UHFFFAOYSA-N Meperidine Chemical compound C=1C=CC=CC=1C1(C(=O)OCC)CCN(C)CC1 XADCESSVHJOZHK-UHFFFAOYSA-N 0.000 description 1
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 1
- 102000014415 Muscarinic acetylcholine receptor Human genes 0.000 description 1
- 108050003473 Muscarinic acetylcholine receptor Proteins 0.000 description 1
- 229940121948 Muscarinic receptor antagonist Drugs 0.000 description 1
- IDBPHNDTYPBSNI-UHFFFAOYSA-N N-(1-(2-(4-Ethyl-5-oxo-2-tetrazolin-1-yl)ethyl)-4-(methoxymethyl)-4-piperidyl)propionanilide Chemical compound C1CN(CCN2C(N(CC)N=N2)=O)CCC1(COC)N(C(=O)CC)C1=CC=CC=C1 IDBPHNDTYPBSNI-UHFFFAOYSA-N 0.000 description 1
- STECJAGHUSJQJN-UHFFFAOYSA-N N-Methyl-scopolamin Natural products C1C(C2C3O2)N(C)C3CC1OC(=O)C(CO)C1=CC=CC=C1 STECJAGHUSJQJN-UHFFFAOYSA-N 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- UIQMVEYFGZJHCZ-SSTWWWIQSA-N Nalorphine Chemical compound C([C@@H](N(CC1)CC=C)[C@@H]2C=C[C@@H]3O)C4=CC=C(O)C5=C4[C@@]21[C@H]3O5 UIQMVEYFGZJHCZ-SSTWWWIQSA-N 0.000 description 1
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 1
- 101710204212 Neocarzinostatin Proteins 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 108010025020 Nerve Growth Factor Proteins 0.000 description 1
- 102000015336 Nerve Growth Factor Human genes 0.000 description 1
- 229940122467 Nerve growth factor antagonist Drugs 0.000 description 1
- ONBWJWYUHXVEJS-ZTYRTETDSA-N Normorphine Chemical compound C([C@@H](NCC1)[C@@H]2C=C[C@@H]3O)C4=CC=C(O)C5=C4[C@@]21[C@H]3O5 ONBWJWYUHXVEJS-ZTYRTETDSA-N 0.000 description 1
- GHCMHMZSMJREIY-MUHJKIFGSA-N OC[C@@H](O)[C@@H](O)[C@H](O)C(=O)CO.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@H]1[C@H](O)[C@@H](O)C(O)O[C@@H]1CO Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)C(=O)CO.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@H]1[C@H](O)[C@@H](O)C(O)O[C@@H]1CO GHCMHMZSMJREIY-MUHJKIFGSA-N 0.000 description 1
- MUBMVGCGOYJTSS-QQPOUJNHSA-N OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@H]1[C@H](O)[C@@H](O)C(O)O[C@@H]1CO Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@H]1[C@H](O)[C@@H](O)C(O)O[C@@H]1CO MUBMVGCGOYJTSS-QQPOUJNHSA-N 0.000 description 1
- 229940127450 Opioid Agonists Drugs 0.000 description 1
- 102000003840 Opioid Receptors Human genes 0.000 description 1
- 108090000137 Opioid Receptors Proteins 0.000 description 1
- 239000008896 Opium Substances 0.000 description 1
- VNQABZCSYCTZMS-UHFFFAOYSA-N Orthoform Chemical compound COC(=O)C1=CC=C(O)C(N)=C1 VNQABZCSYCTZMS-UHFFFAOYSA-N 0.000 description 1
- BRUQQQPBMZOVGD-XFKAJCMBSA-N Oxycodone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C BRUQQQPBMZOVGD-XFKAJCMBSA-N 0.000 description 1
- UQCNKQCJZOAFTQ-ISWURRPUSA-N Oxymorphone Chemical compound O([C@H]1C(CC[C@]23O)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O UQCNKQCJZOAFTQ-ISWURRPUSA-N 0.000 description 1
- DUDKAZCAISNGQN-UHFFFAOYSA-N Oxyphencyclimine Chemical compound CN1CCCN=C1COC(=O)C(O)(C=1C=CC=CC=1)C1CCCCC1 DUDKAZCAISNGQN-UHFFFAOYSA-N 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 208000000450 Pelvic Pain Diseases 0.000 description 1
- 108010081690 Pertussis Toxin Proteins 0.000 description 1
- YQKAVWCGQQXBGW-UHFFFAOYSA-N Piperocaine Chemical compound CC1CCCCN1CCCOC(=O)C1=CC=CC=C1 YQKAVWCGQQXBGW-UHFFFAOYSA-N 0.000 description 1
- 239000004353 Polyethylene glycol 8000 Substances 0.000 description 1
- 229930182780 Polyphenon E Natural products 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 229940127315 Potassium Channel Openers Drugs 0.000 description 1
- KCLANYCVBBTKTO-UHFFFAOYSA-N Proparacaine Chemical compound CCCOC1=CC=C(C(=O)OCCN(CC)CC)C=C1N KCLANYCVBBTKTO-UHFFFAOYSA-N 0.000 description 1
- CAJIGINSTLKQMM-UHFFFAOYSA-N Propoxycaine Chemical compound CCCOC1=CC(N)=CC=C1C(=O)OCCN(CC)CC CAJIGINSTLKQMM-UHFFFAOYSA-N 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 101000857870 Squalus acanthias Gonadoliberin Proteins 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 229920000439 Sulodexide Polymers 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- 102000002689 Toll-like receptor Human genes 0.000 description 1
- 108020000411 Toll-like receptor Proteins 0.000 description 1
- 229940123445 Tricyclic antidepressant Drugs 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 1
- 108010057266 Type A Botulinum Toxins Proteins 0.000 description 1
- 206010046555 Urinary retention Diseases 0.000 description 1
- 206010046798 Uterine leiomyoma Diseases 0.000 description 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- 238000002679 ablation Methods 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000001800 adrenalinergic effect Effects 0.000 description 1
- 239000000464 adrenergic agent Substances 0.000 description 1
- 239000000695 adrenergic alpha-agonist Substances 0.000 description 1
- 239000000808 adrenergic beta-agonist Substances 0.000 description 1
- 229940009456 adriamycin Drugs 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 229960001391 alfentanil Drugs 0.000 description 1
- KGYFOSCXVAXULR-UHFFFAOYSA-N allylprodine Chemical compound C=1C=CC=CC=1C1(OC(=O)CC)CCN(C)CC1CC=C KGYFOSCXVAXULR-UHFFFAOYSA-N 0.000 description 1
- 229950004361 allylprodine Drugs 0.000 description 1
- 229960001349 alphaprodine Drugs 0.000 description 1
- UVAZQQHAVMNMHE-XJKSGUPXSA-N alphaprodine Chemical compound C=1C=CC=CC=1[C@@]1(OC(=O)CC)CCN(C)C[C@@H]1C UVAZQQHAVMNMHE-XJKSGUPXSA-N 0.000 description 1
- 229960002684 aminocaproic acid Drugs 0.000 description 1
- 229940126575 aminoglycoside Drugs 0.000 description 1
- 229960002749 aminolevulinic acid Drugs 0.000 description 1
- 229960003022 amoxicillin Drugs 0.000 description 1
- LSQZJLSUYDQPKJ-NJBDSQKTSA-N amoxicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=C(O)C=C1 LSQZJLSUYDQPKJ-NJBDSQKTSA-N 0.000 description 1
- 229940124326 anaesthetic agent Drugs 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 210000003484 anatomy Anatomy 0.000 description 1
- LKYQLAWMNBFNJT-UHFFFAOYSA-N anileridine Chemical compound C1CC(C(=O)OCC)(C=2C=CC=CC=2)CCN1CCC1=CC=C(N)C=C1 LKYQLAWMNBFNJT-UHFFFAOYSA-N 0.000 description 1
- 229960002512 anileridine Drugs 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001078 anti-cholinergic effect Effects 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000000708 anti-progestin effect Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 230000000842 anti-protozoal effect Effects 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 230000002921 anti-spasmodic effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 229940065524 anticholinergics inhalants for obstructive airway diseases Drugs 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 229960005475 antiinfective agent Drugs 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000003418 antiprogestin Substances 0.000 description 1
- 239000003904 antiprotozoal agent Substances 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- RMTMMKNSPRRFHW-SVAVBUBPSA-N apatorsen Chemical compound N1([C@@H]2O[C@H](COP(O)(=S)OC3C([C@@H](O[C@@H]3COP(O)(=S)OC3C([C@@H](O[C@@H]3COP(O)(=S)OC3C([C@@H](O[C@@H]3COP(O)(=S)OC3[C@H](O[C@H](C3)N3C4=C(C(NC(N)=N4)=O)N=C3)COP(O)(=S)OC3[C@H](O[C@H](C3)N3C4=C(C(NC(N)=N4)=O)N=C3)COP(O)(=S)OC3[C@H](O[C@H](C3)N3C(N=C(N)C(C)=C3)=O)COP(O)(=S)OC3[C@H](O[C@H](C3)N3C(NC(=O)C(C)=C3)=O)COP(O)(=S)OC3[C@H](O[C@H](C3)N3C(N=C(N)C(C)=C3)=O)COP(O)(=S)OC3[C@H](O[C@H](C3)N3C4=C(C(NC(N)=N4)=O)N=C3)COP(O)(=S)OC3[C@H](O[C@H](C3)N3C(N=C(N)C(C)=C3)=O)COP(O)(=S)OC3[C@H](O[C@H](C3)N3C4=C(C(NC(N)=N4)=O)N=C3)COP(O)(=S)OC3[C@H](O[C@H](C3)N3C4=C(C(NC(N)=N4)=O)N=C3)COP(O)(=S)OC3[C@H](O[C@H](C3)N3C(N=C(N)C(C)=C3)=O)COP(S)(=O)OC3[C@H](O[C@H](C3)N3C4=C(C(NC(N)=N4)=O)N=C3)COP(O)(=S)OC3[C@H](O[C@H](C3)N3C(N=C(N)C(C)=C3)=O)COP(O)(=S)OC3C([C@@H](O[C@@H]3COP(O)(=S)OC3C([C@@H](O[C@@H]3COP(O)(=S)OC3C([C@@H](O[C@@H]3COP(O)(=S)OC3C([C@@H](O[C@@H]3CO)N3C4=C(C(NC(N)=N4)=O)N=C3)OCCOC)N3C4=C(C(NC(N)=N4)=O)N=C3)OCCOC)N3C4=C(C(NC(N)=N4)=O)N=C3)OCCOC)N3C4=NC=NC(N)=C4N=C3)OCCOC)N3C(NC(=O)C(C)=C3)=O)OCCOC)N3C(N=C(N)C(C)=C3)=O)OCCOC)N3C4=C(C(NC=N4)=N)N=C3)OCCOC)C(O)C2OCCOC)C=C(C)C(=O)NC1=O RMTMMKNSPRRFHW-SVAVBUBPSA-N 0.000 description 1
- 101150089041 aph-1 gene Proteins 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229960003831 articaine Drugs 0.000 description 1
- 229960000794 baclofen Drugs 0.000 description 1
- NCNRHFGMJRPRSK-MDZDMXLPSA-N belinostat Chemical compound ONC(=O)\C=C\C1=CC=CC(S(=O)(=O)NC=2C=CC=CC=2)=C1 NCNRHFGMJRPRSK-MDZDMXLPSA-N 0.000 description 1
- 229960003094 belinostat Drugs 0.000 description 1
- 229960005274 benzocaine Drugs 0.000 description 1
- VXJABHHJLXLNMP-UHFFFAOYSA-N benzoic acid [2-methyl-2-(propylamino)propyl] ester Chemical compound CCCNC(C)(C)COC(=O)C1=CC=CC=C1 VXJABHHJLXLNMP-UHFFFAOYSA-N 0.000 description 1
- RDJGWRFTDZZXSM-RNWLQCGYSA-N benzylmorphine Chemical compound O([C@@H]1[C@]23CCN([C@H](C4)[C@@H]3C=C[C@@H]1O)C)C1=C2C4=CC=C1OCC1=CC=CC=C1 RDJGWRFTDZZXSM-RNWLQCGYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- NZUPCNDJBJXXRF-UHFFFAOYSA-O bethanechol Chemical compound C[N+](C)(C)CC(C)OC(N)=O NZUPCNDJBJXXRF-UHFFFAOYSA-O 0.000 description 1
- 229960000910 bethanechol Drugs 0.000 description 1
- FLKWNFFCSSJANB-UHFFFAOYSA-N bezitramide Chemical compound O=C1N(C(=O)CC)C2=CC=CC=C2N1C(CC1)CCN1CCC(C#N)(C=1C=CC=CC=1)C1=CC=CC=C1 FLKWNFFCSSJANB-UHFFFAOYSA-N 0.000 description 1
- 229960004611 bezitramide Drugs 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 229920000249 biocompatible polymer Polymers 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- RMRJXGBAOAMLHD-IHFGGWKQSA-N buprenorphine Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]11CC[C@]3([C@H](C1)[C@](C)(O)C(C)(C)C)OC)CN2CC1CC1 RMRJXGBAOAMLHD-IHFGGWKQSA-N 0.000 description 1
- 229960001736 buprenorphine Drugs 0.000 description 1
- 229960003369 butacaine Drugs 0.000 description 1
- IFKLAQQSCNILHL-QHAWAJNXSA-N butorphanol Chemical compound N1([C@@H]2CC3=CC=C(C=C3[C@@]3([C@]2(CCCC3)O)CC1)O)CC1CCC1 IFKLAQQSCNILHL-QHAWAJNXSA-N 0.000 description 1
- 229960001113 butorphanol Drugs 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229960002504 capsaicin Drugs 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 229960000590 celecoxib Drugs 0.000 description 1
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 239000000919 ceramic Substances 0.000 description 1
- 230000003034 chemosensitisation Effects 0.000 description 1
- 239000006114 chemosensitizer Substances 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229940059329 chondroitin sulfate Drugs 0.000 description 1
- 229960001747 cinchocaine Drugs 0.000 description 1
- PUFQVTATUTYEAL-UHFFFAOYSA-N cinchocaine Chemical compound C1=CC=CC2=NC(OCCCC)=CC(C(=O)NCCN(CC)CC)=C21 PUFQVTATUTYEAL-UHFFFAOYSA-N 0.000 description 1
- 229960003405 ciprofloxacin Drugs 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- STJMRWALKKWQGH-UHFFFAOYSA-N clenbuterol Chemical compound CC(C)(C)NCC(O)C1=CC(Cl)=C(N)C(Cl)=C1 STJMRWALKKWQGH-UHFFFAOYSA-N 0.000 description 1
- 229960001117 clenbuterol Drugs 0.000 description 1
- GKEGFOKQMZHVOW-KUTGSRRKSA-M clidinium bromide Chemical compound [Br-].C1([C@H]2CC[N@+](CC2)(C1)C)OC(=O)C(O)(C=1C=CC=CC=1)C1=CC=CC=C1 GKEGFOKQMZHVOW-KUTGSRRKSA-M 0.000 description 1
- 229960005098 clidinium bromide Drugs 0.000 description 1
- GPZLDQAEBHTMPG-UHFFFAOYSA-N clonitazene Chemical compound N=1C2=CC([N+]([O-])=O)=CC=C2N(CCN(CC)CC)C=1CC1=CC=C(Cl)C=C1 GPZLDQAEBHTMPG-UHFFFAOYSA-N 0.000 description 1
- 229950001604 clonitazene Drugs 0.000 description 1
- 229940047766 co-trimoxazole Drugs 0.000 description 1
- 229960003920 cocaine Drugs 0.000 description 1
- 229960004126 codeine Drugs 0.000 description 1
- OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Natural products C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000000599 controlled substance Substances 0.000 description 1
- YLRNESBGEGGQBK-UHFFFAOYSA-N cyclomethycaine Chemical compound CC1CCCCN1CCCOC(=O)C(C=C1)=CC=C1OC1CCCCC1 YLRNESBGEGGQBK-UHFFFAOYSA-N 0.000 description 1
- 229960004741 cyclomethycaine Drugs 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- DUSHUSLJJMDGTE-ZJPMUUANSA-N cyproterone Chemical compound C1=C(Cl)C2=CC(=O)[C@@H]3C[C@@H]3[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)C)(O)[C@@]1(C)CC2 DUSHUSLJJMDGTE-ZJPMUUANSA-N 0.000 description 1
- 229960003843 cyproterone Drugs 0.000 description 1
- 238000009799 cystectomy Methods 0.000 description 1
- 239000002254 cytotoxic agent Substances 0.000 description 1
- 231100000599 cytotoxic agent Toxicity 0.000 description 1
- 229960000766 danazol Drugs 0.000 description 1
- POZRVZJJTULAOH-LHZXLZLDSA-N danazol Chemical compound C1[C@]2(C)[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=CC2=C1C=NO2 POZRVZJJTULAOH-LHZXLZLDSA-N 0.000 description 1
- 229960002677 darifenacin Drugs 0.000 description 1
- HXGBXQDTNZMWGS-RUZDIDTESA-N darifenacin Chemical compound C=1C=CC=CC=1C([C@H]1CN(CCC=2C=C3CCOC3=CC=2)CC1)(C(=O)N)C1=CC=CC=C1 HXGBXQDTNZMWGS-RUZDIDTESA-N 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 229960004281 desmopressin Drugs 0.000 description 1
- NFLWUMRGJYTJIN-NXBWRCJVSA-N desmopressin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSCCC(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(N)=O)=O)CCC(=O)N)C1=CC=CC=C1 NFLWUMRGJYTJIN-NXBWRCJVSA-N 0.000 description 1
- 229950003851 desomorphine Drugs 0.000 description 1
- LNNWVNGFPYWNQE-GMIGKAJZSA-N desomorphine Chemical compound C1C2=CC=C(O)C3=C2[C@]24CCN(C)[C@H]1[C@@H]2CCC[C@@H]4O3 LNNWVNGFPYWNQE-GMIGKAJZSA-N 0.000 description 1
- 201000003892 detrusor sphincter dyssynergia Diseases 0.000 description 1
- 229960003701 dextromoramide Drugs 0.000 description 1
- INUNXTSAACVKJS-OAQYLSRUSA-N dextromoramide Chemical compound C([C@@H](C)C(C(=O)N1CCCC1)(C=1C=CC=CC=1)C=1C=CC=CC=1)N1CCOCC1 INUNXTSAACVKJS-OAQYLSRUSA-N 0.000 description 1
- 229960004193 dextropropoxyphene Drugs 0.000 description 1
- XLMALTXPSGQGBX-GCJKJVERSA-N dextropropoxyphene Chemical compound C([C@](OC(=O)CC)([C@H](C)CN(C)C)C=1C=CC=CC=1)C1=CC=CC=C1 XLMALTXPSGQGBX-GCJKJVERSA-N 0.000 description 1
- 229960003461 dezocine Drugs 0.000 description 1
- VTMVHDZWSFQSQP-VBNZEHGJSA-N dezocine Chemical compound C1CCCC[C@H]2CC3=CC=C(O)C=C3[C@]1(C)[C@H]2N VTMVHDZWSFQSQP-VBNZEHGJSA-N 0.000 description 1
- 239000000032 diagnostic agent Substances 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 229960002069 diamorphine Drugs 0.000 description 1
- RXTHKWVSXOIHJS-UHFFFAOYSA-N diampromide Chemical compound C=1C=CC=CC=1N(C(=O)CC)CC(C)N(C)CCC1=CC=CC=C1 RXTHKWVSXOIHJS-UHFFFAOYSA-N 0.000 description 1
- 229950001059 diampromide Drugs 0.000 description 1
- CURUTKGFNZGFSE-UHFFFAOYSA-N dicyclomine Chemical compound C1CCCCC1C1(C(=O)OCCN(CC)CC)CCCCC1 CURUTKGFNZGFSE-UHFFFAOYSA-N 0.000 description 1
- GUBNMFJOJGDCEL-UHFFFAOYSA-N dicyclomine hydrochloride Chemical compound [Cl-].C1CCCCC1C1(C(=O)OCC[NH+](CC)CC)CCCCC1 GUBNMFJOJGDCEL-UHFFFAOYSA-N 0.000 description 1
- 229960002777 dicycloverine Drugs 0.000 description 1
- RGLYKWWBQGJZGM-ISLYRVAYSA-N diethylstilbestrol Chemical compound C=1C=C(O)C=CC=1C(/CC)=C(\CC)C1=CC=C(O)C=C1 RGLYKWWBQGJZGM-ISLYRVAYSA-N 0.000 description 1
- 229960000452 diethylstilbestrol Drugs 0.000 description 1
- 229960000920 dihydrocodeine Drugs 0.000 description 1
- RBOXVHNMENFORY-DNJOTXNNSA-N dihydrocodeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC RBOXVHNMENFORY-DNJOTXNNSA-N 0.000 description 1
- RHUWRJWFHUKVED-UHFFFAOYSA-N dimenoxadol Chemical compound C=1C=CC=CC=1C(C(=O)OCCN(C)C)(OCC)C1=CC=CC=C1 RHUWRJWFHUKVED-UHFFFAOYSA-N 0.000 description 1
- 229950011187 dimenoxadol Drugs 0.000 description 1
- QIRAYNIFEOXSPW-UHFFFAOYSA-N dimepheptanol Chemical compound C=1C=CC=CC=1C(CC(C)N(C)C)(C(O)CC)C1=CC=CC=C1 QIRAYNIFEOXSPW-UHFFFAOYSA-N 0.000 description 1
- 229950004655 dimepheptanol Drugs 0.000 description 1
- 229950008972 dioxaphetyl butyrate Drugs 0.000 description 1
- LQGIXNQCOXNCRP-UHFFFAOYSA-N dioxaphetyl butyrate Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(C(=O)OCC)CCN1CCOCC1 LQGIXNQCOXNCRP-UHFFFAOYSA-N 0.000 description 1
- SVDHSZFEQYXRDC-UHFFFAOYSA-N dipipanone Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(C(=O)CC)CC(C)N1CCCCC1 SVDHSZFEQYXRDC-UHFFFAOYSA-N 0.000 description 1
- 229960002500 dipipanone Drugs 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- 229960003722 doxycycline Drugs 0.000 description 1
- 238000005553 drilling Methods 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 210000003204 ejaculatory duct Anatomy 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 239000000806 elastomer Substances 0.000 description 1
- 238000010894 electron beam technology Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 229960002236 emepronium Drugs 0.000 description 1
- JEJBJBKVPOWOQK-UHFFFAOYSA-N emepronium Chemical compound C=1C=CC=CC=1C(CC(C)[N+](C)(C)CC)C1=CC=CC=C1 JEJBJBKVPOWOQK-UHFFFAOYSA-N 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- ZOWQTJXNFTWSCS-IAQYHMDHSA-N eptazocine Chemical compound C1N(C)CC[C@@]2(C)C3=CC(O)=CC=C3C[C@@H]1C2 ZOWQTJXNFTWSCS-IAQYHMDHSA-N 0.000 description 1
- 229950010920 eptazocine Drugs 0.000 description 1
- 229960003276 erythromycin Drugs 0.000 description 1
- FRPJXPJMRWBBIH-RBRWEJTLSA-N estramustine Chemical compound ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 FRPJXPJMRWBBIH-RBRWEJTLSA-N 0.000 description 1
- 229960001842 estramustine Drugs 0.000 description 1
- WGJHHMKQBWSQIY-UHFFFAOYSA-N ethoheptazine Chemical compound C=1C=CC=CC=1C1(C(=O)OCC)CCCN(C)CC1 WGJHHMKQBWSQIY-UHFFFAOYSA-N 0.000 description 1
- 229960000569 ethoheptazine Drugs 0.000 description 1
- MORSAEFGQPDBKM-UHFFFAOYSA-N ethylmethylthiambutene Chemical compound C=1C=CSC=1C(=CC(C)N(C)CC)C1=CC=CS1 MORSAEFGQPDBKM-UHFFFAOYSA-N 0.000 description 1
- 229950006111 ethylmethylthiambutene Drugs 0.000 description 1
- 229960004578 ethylmorphine Drugs 0.000 description 1
- 229960003976 etidocaine Drugs 0.000 description 1
- PXDBZSCGSQSKST-UHFFFAOYSA-N etonitazene Chemical compound C1=CC(OCC)=CC=C1CC1=NC2=CC([N+]([O-])=O)=CC=C2N1CCN(CC)CC PXDBZSCGSQSKST-UHFFFAOYSA-N 0.000 description 1
- 229950004538 etonitazene Drugs 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 229960002428 fentanyl Drugs 0.000 description 1
- PJMPHNIQZUBGLI-UHFFFAOYSA-N fentanyl Chemical compound C=1C=CC=CC=1N(C(=O)CC)C(CC1)CCN1CCC1=CC=CC=C1 PJMPHNIQZUBGLI-UHFFFAOYSA-N 0.000 description 1
- 229960004524 fesoterodine fumarate Drugs 0.000 description 1
- 229940126864 fibroblast growth factor Drugs 0.000 description 1
- 229950007979 flufenisal Drugs 0.000 description 1
- MKXKFYHWDHIYRV-UHFFFAOYSA-N flutamide Chemical compound CC(C)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 MKXKFYHWDHIYRV-UHFFFAOYSA-N 0.000 description 1
- 229960002074 flutamide Drugs 0.000 description 1
- 230000004907 flux Effects 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- VZCCETWTMQHEPK-UHFFFAOYSA-N gamma-Linolensaeure Natural products CCCCCC=CCC=CCC=CCCCCC(O)=O VZCCETWTMQHEPK-UHFFFAOYSA-N 0.000 description 1
- VZCCETWTMQHEPK-QNEBEIHSSA-N gamma-linolenic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/CCCCC(O)=O VZCCETWTMQHEPK-QNEBEIHSSA-N 0.000 description 1
- 235000020664 gamma-linolenic acid Nutrition 0.000 description 1
- 229960002733 gamolenic acid Drugs 0.000 description 1
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 1
- 229960002584 gefitinib Drugs 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229940015042 glycopyrrolate Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 108010057806 hemiasterlin Proteins 0.000 description 1
- 229930187626 hemiasterlin Natural products 0.000 description 1
- 201000002802 hemorrhagic cystitis Diseases 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 229960005388 hexylcaine Drugs 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- XPXMKIXDFWLRAA-UHFFFAOYSA-N hydrazinide Chemical compound [NH-]N XPXMKIXDFWLRAA-UHFFFAOYSA-N 0.000 description 1
- LLPOLZWFYMWNKH-CMKMFDCUSA-N hydrocodone Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)CC(=O)[C@@H]1OC1=C2C3=CC=C1OC LLPOLZWFYMWNKH-CMKMFDCUSA-N 0.000 description 1
- 229960000240 hydrocodone Drugs 0.000 description 1
- WTJBNMUWRKPFRS-UHFFFAOYSA-N hydroxypethidine Chemical compound C=1C=CC(O)=CC=1C1(C(=O)OCC)CCN(C)CC1 WTJBNMUWRKPFRS-UHFFFAOYSA-N 0.000 description 1
- 229950008496 hydroxypethidine Drugs 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 229960000908 idarubicin Drugs 0.000 description 1
- 239000012216 imaging agent Substances 0.000 description 1
- 201000001881 impotence Diseases 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- VNFAARJCGSAROU-UHFFFAOYSA-N inaperisone Chemical compound C1=CC(CC)=CC=C1C(=O)C(C)CN1CCCC1 VNFAARJCGSAROU-UHFFFAOYSA-N 0.000 description 1
- 229950005505 inaperisone Drugs 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 229960004187 indoprofen Drugs 0.000 description 1
- 230000004968 inflammatory condition Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 229960002993 ingenol mebutate Drugs 0.000 description 1
- VDJHFHXMUKFKET-WDUFCVPESA-N ingenol mebutate Chemical compound C[C@@H]1C[C@H]2C(C)(C)[C@H]2[C@@H]2C=C(CO)[C@@H](O)[C@]3(O)[C@@H](OC(=O)C(\C)=C/C)C(C)=C[C@]31C2=O VDJHFHXMUKFKET-WDUFCVPESA-N 0.000 description 1
- 229960001361 ipratropium bromide Drugs 0.000 description 1
- KEWHKYJURDBRMN-ZEODDXGYSA-M ipratropium bromide hydrate Chemical compound O.[Br-].O([C@H]1C[C@H]2CC[C@@H](C1)[N@@+]2(C)C(C)C)C(=O)C(CO)C1=CC=CC=C1 KEWHKYJURDBRMN-ZEODDXGYSA-M 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- IFKPLJWIEQBPGG-UHFFFAOYSA-N isomethadone Chemical compound C=1C=CC=CC=1C(C(C)CN(C)C)(C(=O)CC)C1=CC=CC=C1 IFKPLJWIEQBPGG-UHFFFAOYSA-N 0.000 description 1
- 229950009272 isomethadone Drugs 0.000 description 1
- 229960000318 kanamycin Drugs 0.000 description 1
- 229930027917 kanamycin Natural products 0.000 description 1
- SBUJHOSQTJFQJX-NOAMYHISSA-N kanamycin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N SBUJHOSQTJFQJX-NOAMYHISSA-N 0.000 description 1
- 229930182823 kanamycin A Natural products 0.000 description 1
- 229960003029 ketobemidone Drugs 0.000 description 1
- 229960004752 ketorolac Drugs 0.000 description 1
- OZWKMVRBQXNZKK-UHFFFAOYSA-N ketorolac Chemical compound OC(=O)C1CCN2C1=CC=C2C(=O)C1=CC=CC=C1 OZWKMVRBQXNZKK-UHFFFAOYSA-N 0.000 description 1
- 108010045069 keyhole-limpet hemocyanin Proteins 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- RYZCWZZJFAKYHX-LLVKDONJSA-N lanperisone Chemical compound C([C@@H](C)C(=O)C=1C=CC(=CC=1)C(F)(F)F)N1CCCC1 RYZCWZZJFAKYHX-LLVKDONJSA-N 0.000 description 1
- 229950004624 lanperisone Drugs 0.000 description 1
- 150000002605 large molecules Chemical class 0.000 description 1
- 238000000608 laser ablation Methods 0.000 description 1
- 201000010260 leiomyoma Diseases 0.000 description 1
- RCYBMSQOSGJZLO-BGWNEDDSSA-N levophenacylmorphan Chemical compound C([C@]12CCCC[C@H]1[C@H]1CC3=CC=C(C=C32)O)CN1CC(=O)C1=CC=CC=C1 RCYBMSQOSGJZLO-BGWNEDDSSA-N 0.000 description 1
- 229950007939 levophenacylmorphan Drugs 0.000 description 1
- 229960003406 levorphanol Drugs 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- IMYHGORQCPYVBZ-NLFFAJNJSA-N lofentanil Chemical compound CCC(=O)N([C@@]1([C@@H](CN(CCC=2C=CC=CC=2)CC1)C)C(=O)OC)C1=CC=CC=C1 IMYHGORQCPYVBZ-NLFFAJNJSA-N 0.000 description 1
- 229950010274 lofentanil Drugs 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- RQZAXGRLVPAYTJ-GQFGMJRRSA-N megestrol acetate Chemical compound C1=C(C)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 RQZAXGRLVPAYTJ-GQFGMJRRSA-N 0.000 description 1
- 229960004296 megestrol acetate Drugs 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- 229960002409 mepivacaine Drugs 0.000 description 1
- INWLQCZOYSRPNW-UHFFFAOYSA-N mepivacaine Chemical compound CN1CCCCC1C(=O)NC1=C(C)C=CC=C1C INWLQCZOYSRPNW-UHFFFAOYSA-N 0.000 description 1
- 229950007594 meprylcaine Drugs 0.000 description 1
- JLICHNCFTLFZJN-HNNXBMFYSA-N meptazinol Chemical compound C=1C=CC(O)=CC=1[C@@]1(CC)CCCCN(C)C1 JLICHNCFTLFZJN-HNNXBMFYSA-N 0.000 description 1
- 229960000365 meptazinol Drugs 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- YGSVZRIZCHZUHB-COLVAYQJSA-N metazocine Chemical compound C1C2=CC=C(O)C=C2[C@]2(C)CCN(C)[C@@]1([H])[C@@H]2C YGSVZRIZCHZUHB-COLVAYQJSA-N 0.000 description 1
- 229950009131 metazocine Drugs 0.000 description 1
- 229960001797 methadone Drugs 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- LZCOQTDXKCNBEE-IKIFYQGPSA-N methscopolamine Chemical compound C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3[N+]([C@H](C2)[C@@H]2[C@H]3O2)(C)C)=CC=CC=C1 LZCOQTDXKCNBEE-IKIFYQGPSA-N 0.000 description 1
- 229960001383 methylscopolamine Drugs 0.000 description 1
- NPZXCTIHHUUEEJ-CMKMFDCUSA-N metopon Chemical compound O([C@@]1(C)C(=O)CC[C@@H]23)C4=C5[C@@]13CCN(C)[C@@H]2CC5=CC=C4O NPZXCTIHHUUEEJ-CMKMFDCUSA-N 0.000 description 1
- 229950006080 metopon Drugs 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 244000309715 mini pig Species 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 239000000472 muscarinic agonist Substances 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 229940035363 muscle relaxants Drugs 0.000 description 1
- GODGZZGKTZQSAL-VXFFQEMOSA-N myrophine Chemical compound C([C@@H]1[C@@H]2C=C[C@@H]([C@@H]3OC4=C5[C@]23CCN1C)OC(=O)CCCCCCCCCCCCC)C5=CC=C4OCC1=CC=CC=C1 GODGZZGKTZQSAL-VXFFQEMOSA-N 0.000 description 1
- 229950007471 myrophine Drugs 0.000 description 1
- GPXLMGHLHQJAGZ-JTDSTZFVSA-N nafcillin Chemical compound C1=CC=CC2=C(C(=O)N[C@@H]3C(N4[C@H](C(C)(C)S[C@@H]43)C(O)=O)=O)C(OCC)=CC=C21 GPXLMGHLHQJAGZ-JTDSTZFVSA-N 0.000 description 1
- 229960000515 nafcillin Drugs 0.000 description 1
- 229960000805 nalbuphine Drugs 0.000 description 1
- NETZHAKZCGBWSS-CEDHKZHLSA-N nalbuphine Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]1(O)CC[C@@H]3O)CN2CC1CCC1 NETZHAKZCGBWSS-CEDHKZHLSA-N 0.000 description 1
- 229960000938 nalorphine Drugs 0.000 description 1
- 229960002009 naproxen Drugs 0.000 description 1
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 1
- 239000004084 narcotic analgesic agent Substances 0.000 description 1
- QZGIWPZCWHMVQL-UIYAJPBUSA-N neocarzinostatin chromophore Chemical compound O1[C@H](C)[C@H](O)[C@H](O)[C@@H](NC)[C@H]1O[C@@H]1C/2=C/C#C[C@H]3O[C@@]3([C@@H]3OC(=O)OC3)C#CC\2=C[C@H]1OC(=O)C1=C(O)C=CC2=C(C)C=C(OC)C=C12 QZGIWPZCWHMVQL-UIYAJPBUSA-N 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 229940053128 nerve growth factor Drugs 0.000 description 1
- 230000002981 neuropathic effect Effects 0.000 description 1
- 229960004300 nicomorphine Drugs 0.000 description 1
- HNDXBGYRMHRUFN-CIVUWBIHSA-N nicomorphine Chemical compound O([C@H]1C=C[C@H]2[C@H]3CC=4C5=C(C(=CC=4)OC(=O)C=4C=NC=CC=4)O[C@@H]1[C@]52CCN3C)C(=O)C1=CC=CN=C1 HNDXBGYRMHRUFN-CIVUWBIHSA-N 0.000 description 1
- NXFQHRVNIOXGAQ-YCRREMRBSA-N nitrofurantoin Chemical compound O1C([N+](=O)[O-])=CC=C1\C=N\N1C(=O)NC(=O)C1 NXFQHRVNIOXGAQ-YCRREMRBSA-N 0.000 description 1
- 229960000564 nitrofurantoin Drugs 0.000 description 1
- PULGYDLMFSFVBL-SMFNREODSA-N nociceptin Chemical compound C([C@@H](C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O)[C@@H](C)O)NC(=O)CNC(=O)CNC(=O)[C@@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 PULGYDLMFSFVBL-SMFNREODSA-N 0.000 description 1
- 239000002767 noradrenalin uptake inhibitor Substances 0.000 description 1
- 229950011519 norlevorphanol Drugs 0.000 description 1
- 229960004013 normethadone Drugs 0.000 description 1
- WCJFBSYALHQBSK-UHFFFAOYSA-N normethadone Chemical compound C=1C=CC=CC=1C(CCN(C)C)(C(=O)CC)C1=CC=CC=C1 WCJFBSYALHQBSK-UHFFFAOYSA-N 0.000 description 1
- 229950006134 normorphine Drugs 0.000 description 1
- 229950007418 norpipanone Drugs 0.000 description 1
- WCDSHELZWCOTMI-UHFFFAOYSA-N norpipanone Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(C(=O)CC)CCN1CCCCC1 WCDSHELZWCOTMI-UHFFFAOYSA-N 0.000 description 1
- 229960001699 ofloxacin Drugs 0.000 description 1
- 229940124636 opioid drug Drugs 0.000 description 1
- 229960001027 opium Drugs 0.000 description 1
- 229950006098 orthocaine Drugs 0.000 description 1
- 230000001151 other effect Effects 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 210000003101 oviduct Anatomy 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
- 229960002085 oxycodone Drugs 0.000 description 1
- 229960005118 oxymorphone Drugs 0.000 description 1
- 229960002369 oxyphencyclimine Drugs 0.000 description 1
- LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Natural products O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 229960005489 paracetamol Drugs 0.000 description 1
- 210000003899 penis Anatomy 0.000 description 1
- VOKSWYLNZZRQPF-GDIGMMSISA-N pentazocine Chemical compound C1C2=CC=C(O)C=C2[C@@]2(C)[C@@H](C)[C@@H]1N(CC=C(C)C)CC2 VOKSWYLNZZRQPF-GDIGMMSISA-N 0.000 description 1
- 229960005301 pentazocine Drugs 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 229960000482 pethidine Drugs 0.000 description 1
- LOXCOAXRHYDLOW-UHFFFAOYSA-N phenadoxone Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(C(=O)CC)CC(C)N1CCOCC1 LOXCOAXRHYDLOW-UHFFFAOYSA-N 0.000 description 1
- 229950004540 phenadoxone Drugs 0.000 description 1
- ZQHYKVKNPWDQSL-KNXBSLHKSA-N phenazocine Chemical compound C([C@@]1(C)C2=CC(O)=CC=C2C[C@@H]2[C@@H]1C)CN2CCC1=CC=CC=C1 ZQHYKVKNPWDQSL-KNXBSLHKSA-N 0.000 description 1
- 229960000897 phenazocine Drugs 0.000 description 1
- 229960003799 phenazopyridine hydrochloride Drugs 0.000 description 1
- CFBQYWXPZVQQTN-QPTUXGOLSA-N phenomorphan Chemical compound C([C@]12CCCC[C@H]1[C@H]1CC3=CC=C(C=C32)O)CN1CCC1=CC=CC=C1 CFBQYWXPZVQQTN-QPTUXGOLSA-N 0.000 description 1
- 229950011496 phenomorphan Drugs 0.000 description 1
- IPOPQVVNCFQFRK-UHFFFAOYSA-N phenoperidine Chemical compound C1CC(C(=O)OCC)(C=2C=CC=CC=2)CCN1CCC(O)C1=CC=CC=C1 IPOPQVVNCFQFRK-UHFFFAOYSA-N 0.000 description 1
- 229960004315 phenoperidine Drugs 0.000 description 1
- 229940043441 phosphoinositide 3-kinase inhibitor Drugs 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 229960001045 piperocaine Drugs 0.000 description 1
- 229960001286 piritramide Drugs 0.000 description 1
- IHEHEFLXQFOQJO-UHFFFAOYSA-N piritramide Chemical compound C1CC(C(=O)N)(N2CCCCC2)CCN1CCC(C#N)(C=1C=CC=CC=1)C1=CC=CC=C1 IHEHEFLXQFOQJO-UHFFFAOYSA-N 0.000 description 1
- 229940085678 polyethylene glycol 8000 Drugs 0.000 description 1
- 235000019446 polyethylene glycol 8000 Nutrition 0.000 description 1
- 229920000151 polyglycol Polymers 0.000 description 1
- 239000010695 polyglycol Substances 0.000 description 1
- 239000002861 polymer material Substances 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 239000000583 progesterone congener Substances 0.000 description 1
- ZXWAUWBYASJEOE-UHFFFAOYSA-N proheptazine Chemical compound C=1C=CC=CC=1C1(OC(=O)CC)CCCN(C)CC1C ZXWAUWBYASJEOE-UHFFFAOYSA-N 0.000 description 1
- 229950010387 proheptazine Drugs 0.000 description 1
- XJKQCILVUHXVIQ-UHFFFAOYSA-N properidine Chemical compound C=1C=CC=CC=1C1(C(=O)OC(C)C)CCN(C)CC1 XJKQCILVUHXVIQ-UHFFFAOYSA-N 0.000 description 1
- 229950004345 properidine Drugs 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 229950003255 propoxycaine Drugs 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 201000007094 prostatitis Diseases 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000004080 punching Methods 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 210000004994 reproductive system Anatomy 0.000 description 1
- 230000012923 response to hydrostatic pressure Effects 0.000 description 1
- 229950003447 risocaine Drugs 0.000 description 1
- XPYLKZZOBVLVHB-QDKIRNHSSA-N rociverine Chemical compound CCN(CC)CC(C)OC(=O)[C@H]1CCCC[C@]1(O)C1CCCCC1 XPYLKZZOBVLVHB-QDKIRNHSSA-N 0.000 description 1
- 229960001538 rociverine Drugs 0.000 description 1
- CQRYARSYNCAZFO-UHFFFAOYSA-N salicyl alcohol Chemical compound OCC1=CC=CC=C1O CQRYARSYNCAZFO-UHFFFAOYSA-N 0.000 description 1
- STECJAGHUSJQJN-FWXGHANASA-N scopolamine Chemical compound C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-FWXGHANASA-N 0.000 description 1
- 229960002646 scopolamine Drugs 0.000 description 1
- 229960004499 scopolamine hydrobromide Drugs 0.000 description 1
- WTGQALLALWYDJH-MOUKNHLCSA-N scopolamine hydrobromide (anhydrous) Chemical compound Br.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 WTGQALLALWYDJH-MOUKNHLCSA-N 0.000 description 1
- 210000001625 seminal vesicle Anatomy 0.000 description 1
- 230000020341 sensory perception of pain Effects 0.000 description 1
- 239000003772 serotonin uptake inhibitor Substances 0.000 description 1
- 239000012781 shape memory material Substances 0.000 description 1
- 229920002379 silicone rubber Polymers 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 235000011008 sodium phosphates Nutrition 0.000 description 1
- 238000005476 soldering Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 229950002227 stilonium iodide Drugs 0.000 description 1
- 239000004575 stone Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229960004739 sufentanil Drugs 0.000 description 1
- GGCSSNBKKAUURC-UHFFFAOYSA-N sufentanil Chemical compound C1CN(CCC=2SC=CC=2)CCC1(COC)N(C(=O)CC)C1=CC=CC=C1 GGCSSNBKKAUURC-UHFFFAOYSA-N 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 229960003491 sulodexide Drugs 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 229950008160 tanezumab Drugs 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 229960005383 terodiline Drugs 0.000 description 1
- UISARWKNNNHPGI-UHFFFAOYSA-N terodiline Chemical compound C=1C=CC=CC=1C(CC(C)NC(C)(C)C)C1=CC=CC=C1 UISARWKNNNHPGI-UHFFFAOYSA-N 0.000 description 1
- 229960002372 tetracaine Drugs 0.000 description 1
- GKCBAIGFKIBETG-UHFFFAOYSA-N tetracaine Chemical compound CCCCNC1=CC=C(C(=O)OCCN(C)C)C=C1 GKCBAIGFKIBETG-UHFFFAOYSA-N 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229940110309 tiotropium Drugs 0.000 description 1
- LERNTVKEWCAPOY-DZZGSBJMSA-N tiotropium Chemical compound O([C@H]1C[C@@H]2[N+]([C@H](C1)[C@@H]1[C@H]2O1)(C)C)C(=O)C(O)(C=1SC=CC=1)C1=CC=CS1 LERNTVKEWCAPOY-DZZGSBJMSA-N 0.000 description 1
- 229940044616 toll-like receptor 7 agonist Drugs 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 229960004380 tramadol Drugs 0.000 description 1
- TVYLLZQTGLZFBW-GOEBONIOSA-N tramadol Natural products COC1=CC=CC([C@@]2(O)[C@@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-GOEBONIOSA-N 0.000 description 1
- LLPOLZWFYMWNKH-UHFFFAOYSA-N trans-dihydrocodeinone Natural products C1C(N(CCC234)C)C2CCC(=O)C3OC2=C4C1=CC=C2OC LLPOLZWFYMWNKH-UHFFFAOYSA-N 0.000 description 1
- LOIYMIARKYCTBW-OWOJBTEDSA-N trans-urocanic acid Chemical compound OC(=O)\C=C\C1=CNC=N1 LOIYMIARKYCTBW-OWOJBTEDSA-N 0.000 description 1
- LOIYMIARKYCTBW-UHFFFAOYSA-N trans-urocanic acid Natural products OC(=O)C=CC1=CNC=N1 LOIYMIARKYCTBW-UHFFFAOYSA-N 0.000 description 1
- 230000000472 traumatic effect Effects 0.000 description 1
- 239000003029 tricyclic antidepressant agent Substances 0.000 description 1
- RDTKUZXIHMTSJO-UEIGIMKUSA-M triethyl-[2-[4-[(e)-2-phenylethenyl]phenoxy]ethyl]azanium;iodide Chemical compound [I-].C1=CC(OCC[N+](CC)(CC)CC)=CC=C1\C=C\C1=CC=CC=C1 RDTKUZXIHMTSJO-UEIGIMKUSA-M 0.000 description 1
- GOZBHBFUQHMKQB-UHFFFAOYSA-N trimecaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=C(C)C=C1C GOZBHBFUQHMKQB-UHFFFAOYSA-N 0.000 description 1
- 229950002569 trimecaine Drugs 0.000 description 1
- IEDVJHCEMCRBQM-UHFFFAOYSA-N trimethoprim Chemical compound COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 IEDVJHCEMCRBQM-UHFFFAOYSA-N 0.000 description 1
- 229960001082 trimethoprim Drugs 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229930004668 tropane alkaloid Natural products 0.000 description 1
- 150000003813 tropane derivatives Chemical class 0.000 description 1
- 229940046728 tumor necrosis factor alpha inhibitor Drugs 0.000 description 1
- 239000002451 tumor necrosis factor inhibitor Substances 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 1
- 208000000143 urethritis Diseases 0.000 description 1
- 206010046494 urge incontinence Diseases 0.000 description 1
- 210000003741 urothelium Anatomy 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 229950008617 vamicamide Drugs 0.000 description 1
- 210000001177 vas deferen Anatomy 0.000 description 1
- 201000010653 vesiculitis Diseases 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- 238000003466 welding Methods 0.000 description 1
- 238000004804 winding Methods 0.000 description 1
- 229940075420 xanthine Drugs 0.000 description 1
- 229950009268 zinostatin Drugs 0.000 description 1
- 235000021241 α-lactalbumin Nutrition 0.000 description 1
Abstract
Drug delivery devices and methods of administering drugs to patients are provided. A device (50) includes a reservoir (60) containing a drug (58). The reservoir (60) is defined by a wall (64) having a water- permeable portion, such that the water-permeable portion permits water to enter the device (50) and contact the drug (58). A restraining plug (56) closes off an opening of the device (50) such that transient microchannels (62) form between an elastic portion (54) of the device (50) and the restraining plug (56), upon the generation of a sufficient pressure within the reservoir (60), to release the drug (58) from the device (50). Methods of treating patients for neurogenic detrusor overactivity resulting from a spinal cord injury and/or for idiopathic overactive bladder and urinary incontinence are also described.
Description
Drug delivery devices and methods of stering drugs to patients are provided. A device (50) es a reservoir (60) containing a drug (58). The reservoir (60) is d by a wall (64) having a water-permeable portion, such that the water-permeable portion permits water to enter the device (50) and contact the drug (58). A restraining plug (56) closes off an opening of the device (50) such that transient microchannels (62) form between an elastic portion (54) of the device (50) and the restraining plug (56), upon the generation of a sufficient pressure within the reservoir (60), to release the drug (58) from the device (50). Methods of treating patients for neurogenic detrusor overactivity resulting from a spinal cord injury and/or for idiopathic overactive r and urinary incontinence are also described.
NZ 796300 DRUG DELIVERY DEVICES AND METHODS FOR DRUG DELIVERY Cross-Reference to d Applications This ation is a divisional of New Zealand patent application 755862, which is the national phase entry in New Zealand of PCT international application (published as of U.S. Provisional Applications No. 62/453,333, filed February 1, 2017, and 62/480,744, filed April 3, 2017, the disclosures of which are incorporated herein by reference.
Background This disclosure generally relates to l devices deployable in vivo for controlled drug delivery, and more particularly relates to such s having a permeable wall portion and one or more mechanisms for providing controlled drug release from the device.
Many t drug delivery devices rely on one or more orifices in the sidewall or end of the device, to permit the release of a drug therefrom. r, such orifices, especially those disposed in a sidewall of a device, may be susceptible to encrustation and clogging after the drug delivery device is deployed in a patient. A clogged e is undesirable because it often leads to less reproducible drug release, or it may prevent drug release ly. Additionally, orifices disposed in ends of the device provide release only at the terminal portion of the device, which may not be desirable for all device configurations and drug formulations.
In other cases, a drug delivery device may not have a release orifice and release of drug is controlled by diffusion from a matrix material and/or through a wall ng a reservoir of the drug. Such urations, which rely on diffusion, however, may limit the drug release kinetics that can be achieved and/or may limit the range of suitable materials of construction to ones that lack the desired biocompatibility, stability, sterilizability, and mechanical ties, including manufacturability, wall thickness, flexibility, etc.
Accordingly, a need exists for drug delivery devices that overcome one or more of these disadvantages. A need also exists to provide improved methods and drug delivery s for treating patients with idiopathic overactive bladder and urinary incontinence and patients with neurogenic detrusor overactivity resulting from spinal cord injury.
Summary In one aspect, a drug delivery device is provided, including a body that has a wall ng a reservoir defined within the body, the wall having at least one preformed throughhole disposed therein and having a permeable portion, the body including an elastic portion; a drug formulation which includes a drug, the drug formulation being ed within the reservoir; and at least one restraining plug closing off an opening of the body and contacting the elastic portion of the body, the opening being in fluid communication with the reservoir, wherein the water-permeable portion of the wall is configured to permit water to enter the drug delivery device and contact the drug formulation located in the reservoir, wherein release of the drug from the device is controlled by (i) release of the drug through the at least one preformed through-hole in the wall, and (ii) release of the drug through the transient formation of one or more hannels between the elastic portion of the body and the at least one restraining plug, extending to the opening, upon the generation within the reservoir of a hydrostatic pressure effective to form the one or more microchannels.
In another aspect, a drug delivery device is provided, including a tubular body that has a wall bounding a reservoir defined within the body, the wall having a water-permeable portion and an elastic portion having at least one preformed release port disposed therein; a drug formulation which includes a drug, the drug formulation being disposed within the oir, wherein the water-permeable n of the wall s water to enter the drug delivery device and contact the drug formulation d in the reservoir; and at least one restraining plug secured within the oir in t with the elastic portion of the body and adjacent the at least one preformed release port, such that the at least one ining plug ls release of the drug from the device, via the at least one med release port, by the transient formation of one or more microchannels between the elastic portion of the body and the at least one restraining plug, extending to the at least one preformed release port, upon the generation of a hydrostatic pressure within the reservoir effective to form the one or more microchannels.
In yet another aspect, methods of administering a drug to a patient using one of the above-described devices are provided, including inserting the drug delivery device into a lumen or body cavity of a patient; and permitting water influx into the reservoir to develop a pressure in the reservoir effective to cause the drug to flow from the oir and out of the device and into the lumen or body cavity.
In still yet another aspect, a method of treating a patient in need of treatment for neurogenic detrusor overactivity (NDO) resulting from a spinal cord injury (SCI) is provided, including locally administering an effective amount of trospium into the urinary bladder of the patient continuously over a treatment period of 30 to 60 days.
In still yet another aspect, a method of treating a patient in need of ent for idiopathic overactive bladder (iOAB) and y incontinence is provided, including locally administering an effective amount of trospium into the urinary bladder of the patient continuously over a treatment period of 30 to 60 days.
Brief Description of the Drawings Referring now to the gs, which are meant to be exemplary and not ng, and wherein like elements are numbered alike. The detailed description is set forth with reference to the accompanying drawings illustrating examples of the disclosure, in which use of the same reference numerals indicates similar or identical items. Certain embodiments of the t disclosure may include elements, components, and/or configurations other than those rated in the drawings, and some of the elements, components, and/or urations illustrated in the drawings may not be present in certain embodiments. is a cross-sectional side view of one embodiment of an c portion of a device containing a restraining end plug. is a cross-sectional end view of the embodiment of . is a cross-sectional side view of the device of when the oir is not under an osmotic re. is a cross-sectional side view of the device of when the reservoir is under an osmotic pressure. is a cross-sectional side view of one embodiment of a device having a preformed sidewall orifice and two restraining end plugs. is a plan view of one embodiment of a device having a preformed sidewall orifice and two restraining end plugs. is a cross-sectional magnified view of one of the end plugs of . is an exploded perspective view of the end plug of . is a cross-sectional end view of one ment of a drug delivery device. illustrates various embodiments of restraining plugs in accordance with the present disclosure. is a cross-sectional view illustrating the restraining plugs of in use as the end plugs of a drug delivery device. illustrates deployment of a drug delivery device from a deployment instrument. rates deployment of a drug delivery device in a patient. is a plan view of one ment of a drug delivery device having restraining plugs and a preformed release port. is an enlarged cross-sectional view of the device of .
A is a plan view of one embodiment of a drug delivery device having restraining plugs and a preformed release port.
B is an enlarged cross-sectional view of the device of A. is a graph showing drug release rate over time for a drug delivery device tested in the Examples. is a graph showing drug release rate over time for a drug delivery device tested in the Examples. is a graph g drug release rate over time for a drug delivery device tested in the es. is a graph showing drug release rate over time for various drug delivery devices tested in the Examples. is a graph showing cumulative drug release over time for s drug delivery s tested in the Examples. is a graph showing drug release rate over time for various drug delivery devices tested in the Examples. is a graph showing cumulative drug release over time for various drug ry devices tested in the Examples. is a graph showing drug release rate over time for various drug delivery devices tested in the Examples. is a graph showing drug release rate over time for various drug delivery devices tested in the Examples. is a graph showing drug release rate over time for s drug delivery devices tested in the es. is a graph showing drug release rate over time for various drug delivery devices tested in the es. is a graph showing cumulative drug release over time for various drug delivery devices tested in the Examples. is a graph showing percent drug release over time for various drug delivery devices tested in the Examples. is a graph showing drug release rate over time for various drug delivery devices tested in the Examples.
Detailed Description Drug delivery devices 50 having a permeable wall portion 64 bounding a reservoir 60 (also referred to herein as a voir lumen" or a "drug reservoir lumen") containing a payload 58, such as a drug formulation, are ed herein, along with methods for delivering the payload 58 from the device 50. As shown in the water-permeable wall portion 64 may generally be configured to permit water to enter the device and contact the drug formulation (i.e., payload) 58 located in the reservoir 60, to facilitate release of the drug 58 from the device.
For example, osmotically driven water influx into the reservoir 60 may generate a pressure within the reservoir 60 that drives release of the drug 58 from the reservoir 60 via one or more mechanisms. For example, in embodiments described herein, release of the drug 58 from the device may occur through one or more preformed sidewall orifices 66 (see and/or through the transient ion of one or more microchannels 62 leading to a preformed release port 68 or other g (see . In certain embodiments described , ations of these release mechanisms are employed to provide the desired drug release profile and to overcome the antages discovered in devices exclusively relying on one or more preformed orifices for drug release.
In particular, it has been discovered that implantable intravesical drug delivery devices in which preformed orifices in the side or end walls of the device are ed for the release of drug from the device are susceptible to encrustation and clogging of the orifices following esical deployment, or implantation. Thus, in certain embodiments, as shown in drug ry devices 50 of the present disclosure contain one or more predefined orifices 60 in the sidewall or end of the device in ation with a one-way valve structure involving the transient formation of one or more microchannels 62 leading to a preformed release port or other opening, upon the generation of a hydrostatic pressure effective to form the one or more microchannels in the reservoir 60. For example, the generation of a hydrostatic pressure in the reservoir 60 that exceeds the threshold pressure for the transient formation of microchannels 62 may occur when the med orifice(s) 66 is partially or fully clogged or when release through the orifice(s) 66 does not occur quickly enough to relieve the hydrostatic pressure within the reservoir 60. In some embodiments, as shown in FIGS. 9 and 10, a preformed e port 68 in the ll or end of the device is provided in combination with a restraining plug 56 that blocks access to the release port 68, absent the generation of a hydrostatic pressure in the oir effective to form the one or more microchannels 62 ing to the release port 68.
It has been discovered that lled release of drug can be achieved with devices having improved one-way valve e mechanisms, alone or in combination with other release mechanisms. For example, controlled e of drug can be achieved with the transient formation of microchannels through which a fluidized drug can be dispensed from a delivery device. The microchannels form at an interface of device components in se to a hydrostatic pressure developed in a drug reservoir. Drug delivery devices configured to induce and utilize such microchannels (i.e., which are distinct from preformed orifices) have been developed, which avoid or alleviate the potential problems associated with conventional drug release mechanisms, including precision miniature orifices that may increase component cost and the risk of clogging, or that are limited by diffusion through or from another material.
In embodiments, the drug delivery device 50 es a device body 52 having at least one water-permeable wall portion 64 bounding a drug reservoir 60 defined within the body 52.
A drug formulation 58 which comprises a drug is loaded into the defined drug oir 60. The body 52 includes an elastic portion 54 in fluid communication with the drug oir 60. The device 50 further includes a restraining plug 56 that contacts the elastic portion 54 of the body 52 and controls e of the drug 58 from the device 50 by the transient formation of one or more microchannels 62 n the elastic portion 54 of the body 52 and the at least one restraining plug 56.
The term "microchannels," as used , refers to a passageway or system of eways through which drugs can exit the devices bed herein. In embodiments, the microchannels form in response to hydrostatic pressure that accumulates in the water-permeable body due to osmotically driven water ; when the hydrostatic pressure increases above a certain threshold, the microchannels form, thereby forcing at least a portion of drug out of the device and relieving the hydrostatic pressure accumulation in the drug reservoir. The microchannel may collapse at least partially as the hydrostatic re has been relieved. This process repeats itself until all or a substantial portion of the drug has been released, or the osmotically driven water influx is insufficient to continue the process.
The microchannels may form anywhere along the inner surface of the elastic portion of the water-permeable body, thereby significantly and beneficially reducing the likelihood of complete clogging—even when insoluble excipients are used in the drug formulation. ageously, the microchannels, unlike an orifice, may reduce or ate the potential risk of sudden drug discharge when the device is compressed or deformed. For example, when the drug delivery devices are surrounded by body fluid and disposed in an environment that exposes the devices to te external mechanical stress (such as during ion when the device is a deployed esical drug delivery device), drugs are less likely to be discharged through the microchannels.
FIGS. 1A-1D show one embodiment of the microchannels in a drug delivery device.
Device 50 includes a body, or housing, 52 having an elastic portion 54 with a restraining plug 56 inserted into an opening in the body 52 such that the elastic portion 54 is positioned against (around) an outer surface of the restraining plug 56. As indicated by the dashed line arrows, water diffuses through a water-permeable wall 64 of the body 52 and enters the drug reservoir 60, forming fluidized drug 58, which for example may be an aqueous solution comprising the drug 58 initially loaded in the reservoir 60. Hydrostatic pressure in the reservoir 60 causes the fluidized drug 58 to be pushed out of the reservoir 60 between the elastic portion 54 and the restraining plug 56 , through microchannels 62 that are formed therebetween, for example by c deformation of one or both of the interfacing surfaces. illustrates the device in a state in which hydrostatic pressure in the reservoir has not reached the threshold such that any microchannels are formed between the elastic portion 54 and the ining plug 56. In the embodiment illustrated in FIGS. 1A 1B, and 1D, the microchannel 62 is shown as forming between the reservoir 60 and the terminal rmed) opening 72 of the device 50; however, as described below, in some embodiments, the device 50 is ured such that the microchannel 62 forms between the reservoir 60 and a release port 68 defined in the sidewall or a closed end of the device.
The devices, systems, and s disclosed herein, build upon some features and aspects of the devices, systems and methods bed in the following Patent Application ations: U.S. 2016/0199544 (Lee et al.); U.S. 2012/0089122 (Lee et al.); U.S. 2012/0089121 (Lee et al.); U.S. 2011/0152839 (Cima et al.); U.S. 2010/0331770 (Lee et al.); U.S. 2010/0330149 (Daniel et al.); U.S. 2009/0149833 (Cima et al.); and U.S. 2007/0202151 (Lee et al.), which, in pertinent part, are incorporated by reference herein.
The Drug ry Device An embodiment of a drug delivery device is illustrated in FIGS. 3 and 4. The device includes a water-permeable body 52 having a drug reservoir portion 78 and a retention frame portion 76. As used herein, the term "drug reservoir portion" refers to the portion of the device that forms and defines the "drug reservoir" or "drug reservoir lumen". As such, these terms are used with reference to the same or similar and overlapping features of the devices. In , the device 50 is shown in a relatively expanded shape suited for retention in the body, e.g., in the urinary bladder. As shown in the device 700 may also be disposed in a vely lowerprofile shape for deployment through the channel of a deployment instrument 702, such as a cystoscope or other catheter. Following deployment into the body, the device may assume the relatively expanded shape to retain the drug delivery device in the bladder, or other body cavity or lumen.
In some embodiments, the intravesical device comprises a deployment shape and a retention shape. For e, as shown in the device 700 may be elastically deformable between a relatively straightened or uncoiled shape suited for insertion through a lumen into the bladder of the patient (the deployment shape) and a retention shape suited to retain the device within the r. For the purposes of this disclosure, the term "retention shape" generally denotes any shape suited for retaining the device in the bladder, including but not limited to a coiled or "pretzel" shape. A pretzel shape is shown in . The ion shape enables the device to resist becoming entrained in urine and excreted when the patient voids. The terms "relatively expanded shape", "relatively higher-profile shape" may be used interchangeably with "retention shape." rly, the term "relatively lower-profile shape" may be used interchangeably with "deployment shape" and generally denote any shape suited for deploying the drug delivery device into the body, including the linear or ted shape shown in that is suited for deploying the device through the working channel of a catheter, cystoscope, or other deployment instrument oned in a lumen of the body, such as the urethra. In embodiments, the drug delivery device may naturally assume the relatively expanded shape and may be elastically ed, either manually or with the aid of an external apparatus, into the relatively lower-profile shape for ion into the body. Once deployed the device may spontaneously or naturally (e.g., elastically) return to the initial, relatively expanded shape for retention in the body. In some embodiments, the device behaves like a spring, deforming in response to a compressive load (e.g., deforming the device into a deployment shape) but spontaneously returning to a retention shape once the load is removed. In some embodiments, this shape ng functionality of the intravesical device is ed by including a shape retention frame (i.e., a "retention frame") in the device, as described hereinbelow.
In the illustrated ment of the drug reservoir and retention frame ns 78, 76 of the drug delivery device are longitudinally aligned and are coupled to each other (or integrally formed together) along their length, although other configurations are possible. For e, the drug reservoir portion 78 may be attached to the retention frame portion 76 at te points but otherwise may be separate or spaced apart from the retention frame portion As shown in the drug delivery device includes an elastic or flexible device body 52 that defines a drug reservoir lumen 60 and a retention frame lumen 80. The drug reservoir lumen 60 is designed to house a drug formulation, such as a number of solid drug s 158, to form the drug reservoir portion 78. The retention frame lumen 80 is designed to house a retention frame 74 to form the retention frame portion 76. The illustrated lumens 78, 76 are discrete from each other, although other configurations are possible.
As shown in the cross-sectional view of the device body 52 includes a tube or wall 82 that defines the drug reservoir lumen 60 and a tube or wall 84 that defines the retention frame lumen 80. The tubes 82, 84 and lumens 60, 80 can be substantially cylindrical, with the drug reservoir lumen 60 having a relatively larger diameter than the retention frame lumen 80, gh other configurations can be selected based on, for example, the amount of drug to be red, the diameter of the retention frame, and deployment considerations such as the inner diameter of the deployment instrument. The device body 52 may be formed integrally, such as via g or extrusion, although separate construction and ly of the tubes 82, 84 is possible. The wall 84 that defines the ion frame lumen 80 may extend along the entire length of the wall 82 that defines the drug reservoir lumen 60, so that the ion frame lumen 80 has the same length as the drug reservoir lumen 60 as shown, although one wall may be shorter than the other wall in other embodiments. Further, the two walls 82, 84 are attached along the entire length of the device in the illustrated embodiment, although intermittent attachment can be employed. In one e, the wall 82 of the drug oir lumen 60 has an inner diameter of about 1.5 mm and an outer er of about 1.9 mm, while the wall 84 of the retention frame lumen 80 has an inner diameter of about 0.5 mm and an outer diameter of about 0.9 mm. In another example, the wall 82 of the drug reservoir lumen 60 has an inner diameter of about 2.16 mm and an outer diameter of about 2.56 mm. However, the inner and outer diameters of the wall 82 of the drug reservoir lumen 60 and the wall 84 of the retention frame lumen 80 may be any suitable diameter. The cross-sectional area of the entire body of the device 52 may be about 0.035 cm2 or less. However, the cross-sectional area of the entire body of the device 52 may be any suitable dimension.
As shown in , the drug reservoir lumen may be loaded with a number of drug units 158 in a serial arrangement. The drug units may be tablets, such as mini-tablets. For example, between about 10 and about 100 drug units may be loaded, such as between about 30 and about 70 drug units, or more particularly between about 50 and 60 drug units. However, essentially any number of drug units may be used, depending upon the sizes of the reservoir and the drug units. The drug reservoir lumen includes openings, which may be vely circular gs at opposite ends of the drug reservoir lumen. These openings provide ingress for the drug units to be placed into the drug reservoir lumen during device loading and assembly.
Restraining plugs, as described herein, may be disposed in the reservoir through the terminal openings of the device. The restraining plug and elastic portion may be disposed at any suitable position along the length of the drug delivery device. In certain embodiments, as described herein, a restraining plug may be disposed at or near the terminal end of the device. In other embodiments, a restraining plug may be disposed at or near the central portion of the device. In one embodiment, one of the terminal device openings has a restraining plug, and the opposed opening is sealed with a plug or other material that does not permit the formation of microchannels.
In some instances, as shown in FIGS. 1C and 1D, each of the restraining plugs 56 may, as described herein, have an outer diameter that is larger than the inner er of the drug reservoir lumen 60. In some embodiments, as shown in FIGS. 9A and 10A, the restraining plugs 56 may be secured within the drug reservoir lumen 60 at the terminal ends of the device 50, such that the terminal ends or openings of the device 50 are sealed, such as by an adhesive 70 or other suitable securement means. In other ments, as shown in FIGS. 1C-1D, the restraining plugs 56 may be secured within the drug reservoir lumen 60 by an adhesive 70, but without sealing the lumen. In still other embodiments, the restraining plugs may be secured within the drug reservoir lumen by an external clamp disposed about the drug reservoir lumen. The restraining plugs may be d within the drug oir lumen by any means disclosed herein or a combination f, as long as it permits the desired formation of microchannels.
In certain embodiments, each of the restraining plugs may include a cavity for receiving an end portion of the retention frame. In some cases, a number of restraining plugs can be positioned in the openings or ere along the length of the device. The restraining plugs may be silicone plugs, ethylene vinyl acetate plugs, or a combination thereof. In embodiments where one of the restraining plugs is omitted, the opening without the restraining plug is closed with any other suitable biocompatible material. In one example, the material is an ve substance that is placed in the drug reservoir lumen in workable form and cures therein. In some embodiments, a restraining plug is ed into an g of the drug reservoir lumen, and the other g of the drug reservoir lumen is sealed with an adhesive. In other embodiments, both ends of the drug reservoir lumen may be sealed and one or more restraining plugs may be located within the device near the sealed ends or spaced away from the sealed ends.
As shown in the ion frame lumen 80 is loaded with the retention frame 74, which may be an elastic wire. The retention frame 74 may be configured to return spontaneously to a retention shape, such as the illustrated example "pretzel" shape or r coiled shape, such as those disclosed in the patent application publications identified above and incorporated herein by reference. In particular, the retention frame 74 may retain the device in the body, such as in the bladder. For example, the retention frame 74 may have an c limit and modulus that allows the device 50 to be introduced into the body in a relatively lower-profile shape, permits the device to return to the relatively expanded shape once inside the body, and impedes the device from assuming the relatively lower-profile shape within the body in response to expected forces, such as the hydrodynamic forces associated with ction of the detrusor muscle and urination. Thus, the device may be retained in the body once deployed, limiting or prevent accidental expulsion.
The material used to form the device body 52, at least in part, may be elastic or flexible to permit moving the device between deployment and retention shapes. When the device is in the retention shape, the retention frame portion 76 may tend to lie on the interior side of the drug reservoir portion 78, although the retention frame n 76 can be positioned , outside, above, or below the drug reservoir portion 78 in other cases. At least a portion of the material used to form the device body 52 also is water-permeable so that lizing fluid (e.g., urine or other bodily fluid) can enter the drug oir 60 to solubilize the drug units 158 once the device is deployed. For e, silicone, ethylene vinyl acetate (EVA), thermoplastic polyurethanes, or another biocompatible elastomeric material may be used to form the device body.
In one ment in which the drug delivery device is designed to be inserted in the bladder, the drug delivery device is designed to be inserted into (and optionally retrieved from) the bladder through the urethra cystoscopically. Thus, the device may be sized and shaped to fit through a narrow tubular path of a deployment instrument, such as a catheter or cystoscope.
The exact configuration and shape of the drug ry device may be selected depending upon a variety of factors including the specific site of deployment, route of insertion, drug, dosage n, and therapeutic application of the device. The design of the device may minimize the patient’s pain and discomfort, while locally delivering a therapeutically effective dose of the drug to a tissue site (e.g., urothelial tissue) in a patient.
The Device Body/Drug Reservoir Portion As shown in FIGS. 1-3, 9, and 10, the drug delivery device 50 has a body 52, e.g., a housing, that has a drug reservoir 60, which includes a water-permeable wall 64, and that includes an elastic portion 54 for engagement with the one or more restraining plugs 56. The drug reservoir 60 is at least partially d by the water-permeable wall 64. That is, the device includes a "water-permeable body," which, as the phrase is sometimes used herein, includes any structure having at least a portion that is water-permeable. In ments, the water-permeable body is made entirely from a water-permeable material. In other ments, the waterpermeable body is made from a water-permeable material and a non-water-permeable al.
In further embodiments, the water-permeable body is made from a material having at least one water-permeable portion and at least one non-water-permeable portion. As used herein, a wall or material is "water-permeable" when it permits a fluid to enter the drug delivery device, e.g., by transwall diffusion, and contact the drug formulation located in a reservoir within the device body.
The body 52 of the drug ry devices 50 described herein also includes at least one elastic portion 54. The elastic portion 54 of the device body 52 may be the same as or distinct from the permeable portion 64 of the device body 52 described in the preceding paragraph.
In certain ments, as shown in , the restraining plugs 56 t the at least one elastic portion 54 of the device body 52 to close off an opening the body, which the opening is in fluid communication with the drug reservoir 60 within the device, thereby ing the drug 58 within the drug reservoir 60.
In some embodiments, all of the c portions of the device body are contacted with restraining plugs that permit drug release as described herein. In other embodiments, one or more of the elastic portions of the device body are contacted with restraining plugs that permit drug release as bed herein and the remaining elastic portions of the body are sealed by other suitable means, such as a cap, an adhesive, heat-sealing, soldering, solvent welding, or a combination thereof.
Generally, the length of the elastic portion should equal or exceed the length of the portion of the restraining plug that contacts the elastic portion of the device body, so that formation/use of the microchannels is not ded, for example by an inelastic portion of the device body.
In embodiments, the elastic portion 54 of the body 52 is formed from a material that permits the formation of microchannels 62, or micropathways, between the inner surface of the elastic portion 54 and the restraining plug 56 when hydrostatic pressure builds up in the drug reservoir 60. As bed in detail herein, the micropathways may extend along the surface of the ining plug/elastic portion from the drug reservoir to either an unsealed distal opening of the device body, as shown in FIGS. 1-3, or a preformed release port adjacent the restraining plug, as shown in FIGS. 9-10. The elastic portion may include materials that are water-permeable, water-impermeable, or a combination thereof.
In a first aspect, as shown in FIGS. 1A-1D, the drug delivery devices 50 described herein include one or more restraining plugs 56 in contact with the c portion(s) 54 of the device body 52, to permit drug release via the distal opening(s) of the device body, as described in U.S.
Patent Application Publication 2016/0008271 to Lee, which is incorporated by reference herein in relevant part. However, in contrast to the no-orifice (i.e., no predefined aperture system) of U.S. Patent Application Publication 2016/0008271 to Lee, in certain embodiments, as shown in FIGS. 2 and 3A, the devices include at least one preformed through-hole (i.e., e) 66 disposed in a wall of the device body 52.
Thus, in certain embodiments, as shown in FIGS. 1-4, a drug delivery device 50 includes a body 52 that has a wall bounding a reservoir 60 defined within the body 52, the wall having at least one preformed through-hole 66 disposed therein and ing a water-permeable portion 64, the body 52 including an elastic portion 54; a drug formulation 58 which contains a drug, the drug ation 58 being ed within the reservoir 60; and at least one restraining plug 56 closing off an g of the body 52 and contacting the c portion 54 of the body 52, the opening being in fluid communication with the reservoir 60. The permeable portion 64 of the wall is configured to permit water to enter the drug delivery device 50 and contact the drug formulation 58 located in the oir 60 and release of the drug 58 from the device 50 is controlled by at least one of (i) release of the drug 58 through the at least one preformed throughhole 66 (i.e., re, e) in the wall, and (ii) release of the drug through the transient formation of one or more microchannels 62 between the elastic portion 54 of the body 52 and the at least one restraining plug 56, extending to the opening, upon the generation of a hydrostatic pressure effective to form the one or more microchannels 62. In these embodiments, the restraining plugs 56 may be partially or wholly ed at the distal end openings of the device 50. Such systems have been found to provide consistent and reproducible drug release profiles, while providing a relief valve system that beneficially provides release of the drug when the through-hole is partially or fully clogged. Thus, the device may operate to release drug via the preformed orifice unless and until the hydrostatic pressure within the drug reservoir reaches a threshold pressure of the restraining plug(s), at which point release via the restraining plugs occurs. For example, release of the drug through the at least one preformed through-hole may be osmotically driven.
Beneficially, this device design provides drug release at the side and/or center of the device, which provides increased device design flexibility as well as potential manufacturability improvements as compared to devices in which the release of the drug occurs only through the distal openings of the device.
In a second aspect, as shown in FIGS. 9-10, the drug delivery devices 50 described herein e sealed distal ends (shown sealed with adhesive 70), with one or more restraining plugs 56 in contact with the c portion(s) 54 of the device body 52, to permit drug release via preformed e port(s) 68 in the device body 52 (e.g., sidewall) adjacent the restraining plug 56. The elastic portions 54 may be at or near the ends of the device 50 (as shown in FIGS. 9-10), or may be otherwise disposed along the length of the device, such as at or near the center of the . The retraining plug(s) 56 may be situated adjacent the one or more preformed release port(s) 68 in the device body 52, such that the restraining plug(s) 56 cover, and effectively close, the preformed release port(s) 68 when the threshold hydrostatic re within the drug reservoir 60 has not been reached. In such embodiments, the restraining plugs 56 and elastic portions 54 of the device may be similar to those described above and in U.S. Patent Application Publication 2016/0008271 to Lee, except that the one or more microchannels 62 transiently formed upon the drug reservoir 60 reaching a threshold hydrostatic pressure extend from the drug oir 60 to the preformed release ) 68.
Thus, in certain embodiments, as shown in FIGS. 9-10, a drug delivery device 50 includes a tubular body 52 that comprises a wall bounding a reservoir 60 defined within the body, the wall having a water-permeable portion 64 and an elastic portion 54 having at least one preformed release port 68 (e.g., h-hole, re, orifice, slit) disposed therein; a drug formulation 58 which contains a drug, the drug formulation 58 being disposed within the reservoir 60, wherein the water-permeable portion 64 of the wall permits water to enter the drug delivery device and t the drug formulation 58 d in the reservoir 60; and at least one restraining plug 56 secured within the reservoir 60 in contact with the elastic portion 54 of the body 52 and adjacent the at least one preformed release port 68, such that the at least one restraining plug 56 controls release of the drug from the device, via the at least one preformed release port 68, by the ent formation of one or more microchannels 62 between the elastic portion 54 of the body and the at least one restraining plug 56, extending to the at least one preformed release port 68, upon the generation of a hydrostatic pressure within the reservoir 60 effective to form the one or more microchannels 62. In certain of these embodiments, the at least one preformed release port 68 is a through-hole or a slit disposed in the wall of the body 52.
Any suitable number and location of restraining plugs 56 and preformed release ports 68 may be used, to achieve the desired drug e profile. For example, as shown in , the device 50 may include two preformed ports 68, here shown as apertures, spaced 180 degrees from one another in a tubular device body 52, such that a single restraining plug 56 is positioned adjacent both apertures. As shown in , a pair of res 68 and a ponding restraining plug 56 may be provided at or near each distal end of the device. For example, as shown in B, a single preformed port 68, here shown as a slit, may be disposed adjacent each restraining plug 56. As shown in B, a preformed port 68 and a corresponding restraining plug 56 may be provided at or near each distal end of the .
In such embodiments, a suitable adhesive 70, or other sealing means described herein, may be used to seal the ends of the device body. In certain embodiments, the restraining plug 56 is sealed in place via the adhesive 70 or other sealing means sealing the end(s) of the device body, or via another adhesive. Such device s may reduce complexity and variability associated with manufacturing and assembly of the beveled end plug used when release is from the at least partially ed end opening of the device. Further, such release ports allow for the creation of check valves on the side and/or at the middle of the device, allowing drug release from any location along the device, which decreases the limitations of the design. Additionally, locating release of the drug away from the ends of the device beneficially allows for a rounded (i.e., non-trimmed) device end, such as a sphere or ball-shaped end , which reduces imperfections that may serve as tion points for encrustation, at the ends. Further, such device s advantageously allow for increasing the flexibility and bendability of the terminal ends of the device.
In certain embodiments, the device also includes at least one preformed h-hole disposed in the wall of the body, as bed above, in combination with the preformed release port adjacent a restraining plug, such that e of the drug from the device is further controlled by release of the drug through the at least one preformed through-hole in the wall.
In embodiments in which the drug formulation is solid or semi-solid, as described in r detail below, the device may be configured to permit, in vivo, water to diffuse through the water-permeable portion of the wall and into the reservoir to solubilize the drug formulation.
The devices described herein have been discovered to advantageously provide controlled release of drug via these ed one-way valve release mechanisms, alone or in combination with other release mechanisms such as preformed sidewall orifices, which may experience clogging. Thus, the devices described herein provide for a longer duration of drug delivery as compared to devices with sidewall release orifices alone, which may be tible to encrustation.
Specifically, controlled release of drug can be ed with the transient formation of microchannels through which a fluidized drug can be dispensed from a delivery device, either through the distal end opening of the device or through one or more preformed release ports adjacent a restraining plug. The microchannels form at an interface of device components in response to a hydrostatic pressure developed in a drug reservoir, such that the device parameters can be tailored to release drug only when a certain threshold hydrostatic pressure is reached within the drug oir.
To facilitate the ion of microchannels, the elastic portion 54 of the device body 52 and the restraining plugs56 may be formed from materials having a certain elasticity or hardness. In embodiments, the Shore durometer of the elastic portion of the body is lower than the Shore durometer of the restraining plug. In one embodiment, the Shore durometer of the elastic portion of the body is from about 40A to about 60A, and the Shore durometer of the restraining plug is from about 70A to about 100A. In another ment, the Shore durometer of the elastic n of the body is from about 45A to about 55A, and the Shore durometer of the restraining plug is from about 75A to about 85A. In a further embodiment, the Shore durometer of the elastic portion of the body is about 50A, and the Shore durometer of the restraining plug is about 80A. In yet another embodiment, the Shore durometer of the c portion of the body is from about 40A to about 60A, and the Shore durometer of the restraining plug is about 97A. In some embodiments, in which the ining plug is at or near the end of the device and a preformed release port in the device body is adjacent the restraining plug, the ter of the restraining plug may be further d to decrease the rigidity of the end of the device.
In ments, the device body 52 may contain two or more elastic portions 54 having different elasticities that t two or more restraining plug 56 having different elasticities.
This configuration can be useful for controlling drug release from two or more ent reservoirs having drugs of different solubilities, desired release rates, etc. For example, a waterpermeable body may have a first and a second elastic portion made from two different materials having Shore durometers of 45A and 55A, tively, and inserted into the first and the second elastic portion may be a first and a second ining plug made from two ent materials having Shore durometers of 75A and 85A, respectively.
In one ment, the device body is made entirely from an elastic material. In other embodiments, the body is made from at least one elastic material and at least one inelastic al. In further embodiments, the body is made from a material having at least one elastic portion and at least one inelastic n.
The c portion 54 of the device body 52 may be any shape that permits the insertion of a restraining plug 56 and the creation of interference fit between the elastic portion 54 and the plug 56. When viewed in cross-section, the lumen of the elastic n may be non-polygonal.
For example, the cross-section may be round, substantially round, or oval-shaped. In some embodiments, the shape of the lumen of the elastic portion substantially conforms to the shape of the restraining plug.
The device body 52 generally may be made from any biocompatible material, so long as at least a portion of the body 64 is water-permeable. The elastic portion 54 of the body 52 that contacts the restraining plug 56 may be made from any biocompatible material that permits the formation of one or more microchannels 62 through which drug may exit the device 50.
In one embodiment, the device body 52 includes an elongated tube. An interior of the tube may define one or more drug reservoirs 60, and a drug formulation 58 may be housed in the drug reservoir(s) 60. For example, the elongated tube may be annular in shape with the annulus, i.e., the lumen of the tube, serving as the drug oir. In other embodiments, the drug reservoir portion is in a form other than a tube. The release rate of the drug from the drug reservoir portion generally is controlled by the design of the combination of the device components, including but not limited to the materials, dimensions, surface area, preformed release ports/through-holes, and restraining plugs, as well as the particular drug formulation and total mass of drug load, among others.
An example of the drug reservoir portion 78, i.e., a device body, is shown in As shown, the drug reservoir portion 78 may include a body formed from an elastomeric tube 82.
The tube 82 defines a reservoir 60 that contains a number of drug units 158. Into the gs in the ends of the tube 82, restraining plugs are inserted.
In embodiments, the drug reservoir portion 78 and drug reservoir 60 operate as an c pump. In such embodiments, the drug reservoir portion is formed, at least in part, from a water-permeable material. In a preferred embodiment, the water-permeable material is silicone. Following insertion/implantation into a patient’s body, water or urine tes through a wall of the drug reservoir portion. The water enters the reservoir, contacts the drug formulation, forming a fluidized drug (e.g., a drug solution) which can then be dispensed at a controlled rate out of the reservoir through microchannels that form between the restraining plugs and the elastic portion of the drug reservoir portion. The delivery rate and overall performance of the osmotic pump is affected by device parameters, such as the surface area of the drug reservoir portion; the permeability to liquid of the material used to form the drug reservoir portion; the relative ions, shapes, and positions of the preformed release ports/through-holes in the device body; the ve dimensions, shapes, and elasticity or hardness of the restraining plugs and the elastic portion of the drug reservoir lumen; and the drug formulation dissolution profile, among other s. In some embodiments, the device may initially exhibit a zero-order release rate and subsequently may exhibit a reduced, non-zero-order release rate, in which case the overall drug release profile may be determined by the initial zeroorder release rate and the total payload. Representative examples of osmotic pump designs, and equations for selecting such designs, are described in U.S. Patent Application Publication 2009/0149833 to Cima et al.
The drug oir portion may be formed, at least in part, from an elastomeric material, which may permit elastically deforming the device for its ion into a patient, e.g., during its ment h deployment instrument such as a cystoscope or catheter. For e, the tube may be elastically deformed along with the retention frame for intravesical ion, as described in further detail below.
In one embodiment, the drug reservoir portion is formed from a material that is both meric and water-permeable. Examples of materials that are both elastomeric and water- permeable e silicones and thermoplastic polyurethanes known in the art. Other suitable biocompatible materials, including inelastic biocompatible als, also may be used.
The length, diameter, and ess of the drug reservoir portion may be selected based on the volume of drug ation to be contained, the desired rate of delivery of the drug, the intended site of deployment of the device within the body, the desired mechanical integrity for the device, the desired release rate or permeability to water and urine, the desired induction time before onset of l release, and the desired method or route of insertion into the body, among others. The tube wall thickness may be determined based on the mechanical properties and water permeability of the tube material, as a tube wall that is too thin may not have sufficient mechanical ity while a tube wall that is too thick may experience an undesirably long induction time for initial drug release from the device.
In one embodiment, the device body is non-resorbable. It may be formed of medical grade ne tubing, as known in the art. Other suitable non-resorbable materials may be used.
In other embodiments, the device body is at least partially bioerodible. In one embodiment of a bioerodible device, the drug reservoir portion is formed of a biodegradable or bioresorbable polymer. Any suitable biocompatible polymers may be used.
In embodiments in which the drug reservoir portion is haped, the drug reservoir portion tube may be substantially linear and, in some cases, may be substantially cylindrical with a circular or oval cross-section, although square, triangle, hexagon, and other polygonal crosssectional shapes can be used, among others.
In one embodiment, the drug reservoir portion 78 has le reservoirs. Each reservoir may be defined by a portion of the drug reservoir inner surface and at least one ion. In ments in which the drug reservoir portion is tube-shaped, the partition may be a partition structure or plug inserted into the tube, such as a cylinder, sphere, or disk, among others, in which case the partition structure may have a larger cross-section than the tube, securing the partition structure in place and segregating adjacent reservoirs. The partition may be non-porous or semi-porous, sorbable or resorbable and may be formed of a material described herein with nce to the restraining plugs. The partition also may be formed in the tube, such as by molding. For example, one or more webs may extend through the tube along its length to segregate axial reservoirs that extend along the length of the tube. The partition also may be a structure that joins two different tubes that serve as separate reservoirs.
The multiple reservoirs permit segregating two or more different drug formulations in different reservoirs, delivering a single drug from different reservoirs at different rates or times following deployment, or combinations thereof. For example, two different reservoirs may be in communication with two ent restraining plugs having different configurations, as described herein, which permit the drugs in the two ent oirs to be released at different rates.
The two different reservoirs also may house the same or different drug formulations in the same or different forms (such as liquid, semi-solid, and solid), or combinations thereof. Coatings or sheaths also may be provided along different portions of a single drug reservoir or along different drug reservoirs housing the same or different drug formulations. The coatings or s may be used to alter the water-permeability of the water-permeable body. These embodiments can be combined and varied to achieve the d release profile of the desired drug.
For example, the onset of release of two doses in ent reservoirs can be staged by uring the device accordingly, such as by using different materials (e.g., materials with different water-permeabilities) for portions of the tube defining different reservoirs, by placing drugs with different solubilities in the reservoirs, or by placing drugs with different forms in the reservoirs, such as a liquid form for immediate e and a solid form to be solubilized in vivo prior to release. Thus, the device may release some drug relatively quickly after deployment while other drug may experience an induction time before beginning e.
Preformed Release Apertures/Ports In some embodiments, the device includes one or more ports (e.g., apertures, es, slits, and the like) for dispensing the drug, such as via generation of an osmotic pressure within the drug oir, as described herein. The apertures may be spaced along the tube to provide a passageway for release of the drug formulation. The apertures or orifices may be positioned through a sidewall of the tube. The apertures may be in fluid communication with one or more reservoirs (as illustrated by orifice 66 in FIGS. 2 and 3A) or may be nt a restraining plug (as rated by ports 68 in FIGS. 9 and 10), as described herein.
An embodiment of an aperture 66 is shown on the drug reservoir portion 78 in .
The aperture 66 may be located about a middle of the drug reservoir portion 78 or adjacent to an end of the drug reservoir 60, which may affect the ease of loading solid drug units 158 into the drug reservoir portion 78 as described below. The apertures may be positioned away from a portion of the tube that will be folded during insertion to limit tearing of degradable membranes on the apertures.
The size, number, and placement of the apertures may be selected to provide a controlled rate of release of the drug. A device that operates primarily as an osmotic pump may have one or more apertures sized small enough to reduce diffusion of the drug through the aperture(s), yet large enough and spaced riately along the tube to reduce the buildup of hydrostatic pressure in the tube. Within these aints, the size and number of res for a single device (or oir) can be varied to achieve a selected release rate. In exemplary embodiments, the diameter of the aperture is n about 20 μm and about 500 μm, such as between about μm and about 300 μm, and more particularly between about 30 μm and about 200 μm. In one particular example, the aperture has a diameter between about 100 μm and about 200 μm, such as about 150 μm. In one particular example, the aperture has a diameter between about 25 μm and about 100 μm, such as about 75 μm. A single device may have apertures of two or more different sizes. The aperture may be circular, although other shapes are possible and envisioned, with the shape typically depending on manufacturing considerations. es of processes for forming the apertures include mechanical punching, laser drilling, laser ablation, and g.
The aperture may slightly taper from an exterior to an interior of the tube, and the aperture may be created either before or after the drug is loaded into the tube.
In some embodiments, as shown in , the preformed release port 68 is a slit in the device body 52, which is configured to provide an outlet for the drug 58 upon generation of a pressure sufficient to stretch the c portion 54 of the body 52 in which the port 68 is formed to open the slit and thereby provide a through-hole for the drug on. Such a slit may be configured to function as a y valve, permitting release out from the device when opened by internal pressure and otherwise remaining closed so that external fluids do not pass into the device.
Restraining Plugs The restraining plugs 56 may have any shape suitable for placement in the one or more elastic portions 54 of the body 52 that permits the formation of microchannels 62 as described herein. In embodiments, the restraining plugs 56 are cylindrical or substantially cylindrical. As used herein, the term "substantially cylindrical" refers to any shape that is non-polygonal when viewed in section. In other ments, the restraining plugs are partially cylindrical or substantially cylindrical, and have at least one portion that is wedged, tapered, angled, or rounded. In embodiments, the restraining plugs are solid, not . depicts a series of restraining plugs 502, 503, 504, 505, and 506 having ent shapes. depicts the restraining plugs 502, 503, 504, 505, and 506 inserted into a tubeshaped elastic portion 501 of a device body. When the restraining plug has a wedged, tapered, angled, or rounded surface, these surfaces may allow the microchannels described herein to form more easily. Not wishing to be bound by any particular theory, it is believed that the wedged, tapered, angled, or rounded surfaces may e a preferential path for osmotic flow along or near such surfaces. As a result, less hydrostatic pressure may be required to create one or more microchannels between the restraining plug and the elastic portion of the water-permeable body.
Generally, the restraining plugs may have one or more wedged, tapered, , or rounded surfaces on one side or both sides of the restraining plugs’ longitudinal axis. In embodiments, the angle between the longitudinal surface of the restraining plug and the surface of the wedged, d, angled, or rounded portion may be from about 30° to about 60°.
As shown in the wedged, tapered, angled, or rounded surfaces of the restraining plugs 502, 503, 504, 505, 506 can be inserted into the end of the tube-shaped elastic portion 501 so that the wedged, d, , or rounded surfaces of the ining plugs are in communication with the interior (drug reservoir) of the drug delivery devices. In the d base of the restraining plugs faces outward, as an exterior surface of the drug delivery devices. Alternatively, in other embodiments, the position may be reversed, so that the wedged, tapered, angled, or rounded surfaces of the restraining plug face outward, as an exterior surface of the drug delivery devices, while the base of the ining plug is in communication with the or (drug oir) of the drug ry devices. In this position, the wedged, tapered, angled, or rounded surfaces of the restraining plugs may create a void space at or near the end of the elastic portion. The void space or a portion thereof may host an adhesive, clamp, plug, or other known means for securing the restraining plug, as illustrated in FIGS. 3A-3C.
In certain embodiments, the c portion of the body and the restraining plug may be disposed at a location of the device other than at the terminal end.
The restraining plugs 56 should contact the elastic portions 54 of the water-permeable body 52 in a manner that prohibits the ining plug 56 from being expelled from the elastic portion 54 when the device 50 is compressed in the body after deployment and/or when a hydrostatic force is exerted on the restraining plug 56. In embodiments, the restraining plug 56 and the elastic portion 54 are secured together by an interference fit, e.g., by frictional engagement, with one another, alone or optionally with the aid of an adhesive. The restraining plug 56 should remain in the c portion 54 of the water-permeable body 52 when the device 50 is elastically deformed between its retention shape and relatively straightened shape.
In a red embodiment, the restraining plugs 56 do not migrate within the elastic portions 54 of the device body 52 after deployment and during drug e. In other embodiments, the restraining plugs 56 do migrate within the elastic portions 54 of the waterpermeable body 52 after deployment and during drug release. Migration of the restraining plugs 56 can be ted as long as the drug release is not rably affected.
In embodiments, the cross-sectional shape of the restraining plugs 56 substantially ms to the inner dimensions of the elastic portion 54 of the device body 52. In other embodiments, the outer diameter of the restraining plugs 56 s the inner diameter of the elastic portion 54 of the device body 52. The phrase "inner diameter," as used herein, is not intended to imply that the elastic portion is always circular when viewed in cross-section; instead, the term refers to the largest diameter or major axis of the lumen of the elastic n of the water-permeable body. Similarly, the phrase "outer diameter," as used , is not intended to imply that the restraining plug, when viewed in cross-section, is always circular; instead, the term refers to the largest diameter or major axis of the cross-section of the ining plug or its base.
In one embodiment, the outer diameter of the restraining plug exceeds the inner diameter of the c portion of the device body by at least 3 percent. In another embodiment, the outer diameter of the restraining plug exceeds the inner diameter of the elastic portion of the device body by at least 5 percent. In yet another embodiment, the outer diameter of the restraining plug exceeds the inner diameter of the elastic n of the device body by at least 10 percent. In a further embodiment, the outer diameter of the restraining plug exceeds the inner diameter of the elastic portion of the device body by at least 15 t. In a still further embodiment, the outer diameter of the restraining plug exceeds the inner diameter of the elastic portion of the device body by at least 20 percent. In a particular embodiment, the outer diameter of the restraining plug exceeds the inner diameter of the elastic portion of the body by at least 25 percent.
In one embodiment, the outer diameter of the restraining plug exceeds the inner diameter of the elastic portion of the device body by about 5 percent, and the inner diameter of the elastic portion of the device body is between 2.1 and 2.2 mm, (e.g., 2.16 mm) and the outer diameter of the restraining plug is between 2.2 and 2.3 mm (e.g., 2.27 mm). The restraining plug, in this embodiment, has a length of from about 2.5 mm to about 5 mm.
In another embodiment, the outer diameter of the restraining plug exceeds the inner diameter of the c portion of the water-permeable body by about 28 percent. For example, in one case, the inner diameter of the elastic portion of the permeable body is between 2.1 and 2.2 mm (e.g., 2.16 mm), and the outer diameter of the restraining plug is between 2.7 and 2.8 mm (e.g., 2.77 mm). The restraining plug, in this embodiment, has a length of from about 2.5 mm or 5 mm long.
The restraining plugs may be of any length that is suited for ng the ion of microchannels between the ining plug and the elastic portion of the device body. The outer surface of the restraining plug may contact the inner surface of the elastic portion of the device body along the entire length of the restraining plug or for only a portion of the restraining plug’s length. For example, the outer surface of a restraining plug shaped like a cylinder may contact the inner surface of the opening in the elastic portion of the water-permeable body along the entire length of the restraining plug. The outer surface of a restraining plug having one or more wedged, angled, or tapered surfaces, however, may only contact the inner surface of the elastic portion of the water-permeable body along a portion of the ining plug’s overall length, as shown, for example, in FIGS. 3 and 6.
In embodiments, the length of the restraining plug may be from about 2 mm to about 10 mm, from about 2 mm to about 8 mm, from about 2 to about 6 mm, or from about 2.5 mm to about 5 mm.
Generally, the inner surface of the elastic portion of the water-permeable body and the restraining plug may be shaped so that the restraining plug and the elastic portion of the waterpermeable body remain in t with each other during deployment. In some embodiments, as shown in ve 70 may be used to secure er the elastic portion 54 of the waterpermeable body 52 and the ining plug 56. A single portion or one or more discrete portions of adhesive may be used as long as the amount and placement of adhesive does not undesirably impact the drug release as described herein. In other ments, the restraining plug may be secured mechanically. For example, an external clamp may be used to secure together the elastic portion of the permeable body and the restraining plug. Any suitable clamp may be used as long as it does not undesirably impact tolerability of the device to the patient or the drug release as described herein. When the restraining plug is secured ically, with ve, or both, it may be necessary to form the elastic portion or the restraining plug or both with a softer material to ensure the formation of microchannels.
The restraining plugs may be made from any biocompatible material or combination of biocompatible materials that permits the release of drug from the device as described herein. For example, the restraining plugs may be made from a polymer, such as silicone or ethylene vinyl acetate, a ceramic, an adhesive, or a combination thereof.
In certain embodiments, the restraining plugs are coated with a material to inhibit undesired bonding between the inner surface of the elastic portion and the restraining plug, such as may occur with n ric als when the assembled device is sterilized, e.g., by gamma irradiation. For example, the restraining plugs may be silicone and coated with ne, such as parylene C.
The Retention Frame Portion In a preferred embodiment, as shown in FIGS. 3 and 4, the drug delivery device 50 es a retention frame portion 76. The ion frame portion 76 is associated with the drug reservoir portion 78 and permits retaining the drug reservoir portion 78 in the body, such as in the bladder. The retention frame portion 76 may include a retention frame 74 that is deformable between a relatively expanded shape and a relatively lower-profile shape. For example, the retention frame 74 may naturally assume the relatively expanded shape, may be manipulated into the relatively lower-profile shape for insertion into the body, and may spontaneously return to the vely expanded shape upon insertion into the body. The retention frame 74 in the relatively expanded shape may be shaped for ion in a body cavity, and the retention frame 74 in the relatively lower-profile shape may be shaped for insertion into the body through the working l of a deployment instrument such as a catheter or cystoscope. To achieve such a result, the retention frame 74 may have an elastic limit, modulus, and/or spring constant selected to impede the device from assuming the relatively lower-profile shape once deployed. Such a configuration may limit or t accidental expulsion of the device from the body under expected forces. For example, the device may be retained in the bladder during urination or contraction of the detrusor .
In a preferred embodiment, the retention frame 74 includes or consists of an elastic wire.
For e, in the embodiment shown in FIGS. 3 and 4, the retention frame 74 is an elastic wire formed from a superelastic alloy, such as nitinol, and surrounded by the wall 84 of the retention frame lumen 80, which forms a protective sheath about the retention frame 74. The wall 84 may be formed from a polymer material, such as silicone. In some other embodiments, the retention frame may be an elastic wire formed from a superelastic alloy, such as nitinol, that is covered in a polymer coating such as a silicone sheath and is attached to the drug reservoir portion. In still other ments, the elastic wire may be formed of a relatively low modulus elastomer.
In some embodiments, the retention frame lumen 80 may include the retention frame 74 and a filling material, such as a polymer filling. An example filling material is a silicone adhesive, such as MED3-4213 by Nusil Technology LLC, although other filling materials may be used. The filling material may tely or partially fill the void in the retention frame lumen 80 about the retention frame 74. For example, the filling material may be poured into the retention frame lumen 80 about the retention frame 74 and may cure therein. The filling material may reduce the tendency of the drug reservoir lumen 60 to stretch along, or twist or rotate about, the retention frame 74, while maintaining the drug reservoir lumen 60 in a ed orientation with reference to the retention frame 74. The filling material is not necessary, however, and may be omitted.
When the retention frame 74 is in the relatively expanded shape, such as the coiled shape shown in , the device 50 may occupy a space having dimensions suited to impede expulsion from the bladder. When the retention frame is in the vely lower-profile shape, such as the elongated shape shown in the device 700 may occupy a space suited for insertion into the body, such as h the working channel of a deployment instrument 702.
The properties of the elastic wire cause the device to function as a , deforming in response to a compressive load but neously returning to its initial shape once the load is removed.
A ion frame that assumes a pretzel shape may be relatively ant to compressive forces. The pretzel shape essentially comprises two sub-circles, each having its own r arch and sharing a common larger arch. When the pretzel shape is first compressed, the larger arch s the ty of the compressive force and begins deforming, but with ued compression the smaller arches overlap, and subsequently, all three of the arches resist the compressive force. The resistance to compression of the device as a whole ses once the two sub-circles overlap, impeding se and g of the device as the bladder contracts during urination.
In embodiments in which the retention frame comprises a shape-memory material, the material used to form the frame may "memorize" and spontaneously assume the relatively expanded shape upon the application of heat to the device, such as when exposed to body temperatures upon entering the bladder.
The retention frame may be in a form having a high enough spring nt to retain the device within a body cavity, such as the bladder. A high modulus material may be used, or a low modulus material. Especially when a low-modulus material is used, the retention frame may have a diameter and/or shape that provides a spring constant t which the frame would significantly deform under the forces of urination. For example, the retention frame may include one or more windings, coils, spirals, or combinations thereof, specifically designed to achieve a desirable spring nt as described in U.S. Application Publication 2009/0149833 to Cima et The retention frame may have a two-dimensional structure that is substantially confined to a plane, a three-dimensional structure, such as a structure that occupies the or of a spheroid, or some combination thereof.
Drug Formulations The term "drug" as used herein encompasses any suitable ceutically active ingredient. The drug may be small molecule, macromolecule, biologic, or metabolite, among other forms/types of active ingredients. The drug described herein includes its alternative forms, such as salt forms, free acid forms, free base forms, and hydrates. The drug may be formulated with one or more pharmaceutically able excipients known in the art. Non-limiting examples of the drug include gemcitabine, oxaliplatin, and/or another chemotherapeutic agent; trospium and/or another antimuscarinic agent; and/or lidocaine and/or another anesthetic agent.
In one embodiment, the first compartment may be loaded with two or more types of drug tablets (e.g., different drugs), so that a combination of drugs may be delivered.
In embodiments, the drug is one used to treat pain. A variety of anesthetic agents, analgesic agents, and combinations thereof may be used. In one embodiment, the drug is an anesthetic agent. The anesthetic agent may be a cocaine analogue. The etic agent may be an aminoamide, an aminoester, or combinations thereof. Representative examples of aminoamides or class anesthetics include ine, bupivacaine, aine, cinchocaine, etidocaine, pivacaine, ine, caine, prilocalne, ropivacaine, and trimecaine.
Representative examples of aminoesters or class anesthetics include alne, benzocaine, butacaine, procaine, cocaine, cyclomethycaine, dimethocaine, hexylcaine, larocaine, meprylcaine, toxycaine, orthocaine, piperocaine, procaine, proparacaine, propoxycaine, proxymetacaine, risocaine, and tetracaine. The drug also can be an antimuscarinic compound that exhibits an anesthetic effect, such as oxybutynin or erine. In embodiments, the analgesic agent includes an opioid. Representative examples of opioid agonists include alfentanil, allylprodine, alphaprodine, anileridine, benzyl morphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, di methylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene fentanyl, heroin, hydrocodone, orphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, ne, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, papavereturn, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, dine, piritramide, proheptazine, promedol, properidine, am, propoxyphene, sufentanil, ne, tramadol, pharmaceutically acceptable salts thereof, and mixtures thereof. Other opioid drugs, such as mu, kappa, delta, and nociception opioid receptor agonists, are contemplated.
Representative examples of other suitable pain relieving agents include such agents as salicyl alcohol, phenazopyridine hydrochloride, acetaminophen, acetylsalicylic acid, flufenisal, ibuprofen, indoprofen; indomethacin, naproxen.
In certain embodiments, the drug is one used to treat inflammatory conditions such as interstitial cystitis, radiation cystitis, painful bladder syndrome, prostatitis, urethritis, postsurgical pain, and kidney stones. miting examples of drugs for these conditions include lidocaine, aminoglycans (e.g., chondroitin sulfate, sulodexide), pentosan polysulfate sodium (PPS), yl ide (DMSO), oxybutynin, mitomycin C, heparin, flavoxate, ketorolac, or a combination thereof. Other non-limiting examples of drugs that may be used in the treatment of IC include nerve growth factor monoclonal dy (MAB) antagonists, such as Tanezumab, and calcium channel alphadelta modulators, such as PD-299685 or gabepentin.
In certain embodiments, the drug is one used to treat urinary incontinence, ncy, or urgency, including urge incontinence and neurogenic incontinence, as well as itis. Drugs that may be used include anticholinergic agents, antispasmodic agents, anti-muscarinic agents, -2 ts, alpha adrenergics, anticonvulsants, norepinephrine uptake inhibitors, serotonin uptake inhibitors, calcium l rs, potassium channel openers, and muscle relaxants.
Representative examples of suitable drugs for the treatment of incontinence include oxybutynin, S-oxybutylin, emepronium, verapamil, imipramine, flavoxate, atropine, propantheline, tolterodine, rociverine, clenbuterol, darifenacin, line, trospium, amin, propiverine, desmopressin, vamicamide, clidinium bromide, dicyclomine HCl, glycopyrrolate aminoalcohol ester, ipratropium bromide, olate bromide, methscopolamine bromide, scopolamine hydrobromide, iotropium bromide, fesoterodine fumarate, 03 (Yamanouchi Co., Japan), lanperisone (Nippon Kayaku Co., Japan), inaperisone, NS-21 (Nippon Shinyaku Orion, Formenti, Japan/Italy), NC-1800 (Nippon Chemiphar Co., Japan), Z D-6169 (Zeneca Co., United Kingdom), and stilonium iodide.
In certain embodiments, the drug is one used to treat urinary tract cancer, such as bladder cancer and prostate cancer. Drugs that may be used include antiproliferative agents, cytotoxic agents, chemotherapeutic agents, or a combination f. Representative examples of drugs which may be suitable for the treatment of urinary tract cancer include Bacillus Calmette Guerin (BCG) vaccine, cisplatin, bicin, valrubicin, gemcitabine, mycobacterial cell wall-DNA complex (MCC), methotrexate, vinblastine, thiotepa, mitomycin, fluorouracil, lide, diethylstilbestrol, estramustine, megestrol acetate, cyproterone, flutamide, a selective estrogen receptor modulators (i.e. a SERM, such as tamoxifen), botulinum toxins, and cyclophosphamide.
The drug may be a biologic, and it may comprise a monoclonal antibody, a TNF inhibitor, an anti-leukin, or the like. The drug also may be an modulator, such as a TLR agonist, including mod or another TLR7 agonist. The drug also may be a kinase inhibitor, such as a fibroblast growth factor or-3 (FGFR3)-selective tyrosine kinase inhibitor, a phosphatidylinositol 3 kinase (PI3K) inhibitor, or a mitogen-activated protein kinase (MAPK) inhibitor, among others or combinations thereof. Other examples include celecoxib, erolotinib, gefitinib, paclitaxel, polyphenon E, valrubicin, neocarzinostatin, apaziquone, Belinostat, Ingenol mebutate, Urocidin (MCC), Proxinium (VB 4845), BC 819 (BioCancell Therapeutics), Keyhole limpet haemocyanin, LOR 2040 (Lorus Therapeutics), urocanic acid, OGX 427 enex), and SCH 721015 (Schering-Plough). Other intravesical cancer treatments include small les, such as Apaziquone, adriamycin, AD-32, doxorubicin, docetaxel, epirubicin, gemcitabine, HTI-286 (hemiasterlin ue), idarubicin, γ-linolenic acid, ntrone, meglumine, and thiotepa; large molecules, such as Activated macrophages, activated T cells, EGF-dextran, HPC-doxorubicin, IL-12, IFN-a2b, IFN-γ, α-lactalbumin, p53 adenovector, TNFα; combinations, such as Epirubicin+BCG, IFN+farmarubicin, Doxorubicin+5-FU (oral), BCG+IFN, and Pertussis toxin+cystectomy; activated cells, such as macrophages and T cells; intravesical infusions such as IL-2 and Doxorubicin; chemosensitizers, such as BCG+antifirinolytics (paramethylbenzoic acid or aminocaproic acid) and Doxorubicin+verapimil; diagnostic/imaging agents, such as Hexylaminolevulinate, 5- aminolevulinic acid, Iododexyuridine, HMFG1 Mab+Tc99m; and agents for the management of local toxicity, such as Formaline (hemorrhagic cystitis).
In certain embodiments, the drug is one used to treat infections involving the bladder, the prostate, and the urethra. Antibiotics, antibacterial, antifungal, antiprotozoal, antiseptic, antiviral and other antiinfective agents can be administered for treatment of such infections.
Representative examples of drugs for the treatment of infections include mitomycin, ciprofloxacin, xacin, ofloxacin, methanamine, nitrofurantoin, llin, amoxicillin, nafcillin, trimethoprim, sulfonamides trimethoprimsulfamethoxazole, erythromycin, doxycycline, idazole, tetracycline, kanamycin, llins, cephalosporins, and aminoglycosides.
In n embodiments, the drug is one used to treat fibrosis of a urinary site, such as the bladder or . Representative examples of drugs for the ent of fibroids include pentoxphylline (xanthine ue), antiTNF, antiTGF , GnRH ues, exogenous progestins, antiprogestins, selective estrogen receptor modulators, danazol and .
In certain embodiments, the drug is one used to treat neurogenic bladder. Representative examples of such drugs include analgesics or anaesthetics, such as lidocaine, bupivacaine, mepivacaine, prilocalne, articaine, and ropivacaine; anticholinergics; antimuscarinics such as oxybutynin or propiverine; a vanilloid, such as capsaicin or resiniferatoxin; antimuscarinics such as ones that act on the M3 muscarinic acetylcholine receptor (mAChRs); antispasmodics including GABAB agonists such as baclofen; botulinum ; capsaicins; α-adrenergic antagonists; anticonvulsants; nin ke inhibitors such as amitriptyline; and nerve growth factor antagonists. In various embodiments, the drug may be one that acts on bladder afferents or one that acts on the efferent cholinergic ission, as described in Reitz et al., Spinal Cord 42:267-72 (2004).
In certain embodiments, the drug is one used to treat incontinence due to neurologic detrusor overactivity and/or low compliant detrusor. Examples of these types of drugs include bladder relaxant drugs (e.g., oxybutynin (antimuscarinic agent with a nced muscle relaxant activity and local anesthetic activity), propiverine, impratroprium, tiotropium, trospium, terodiline, tolterodine, propantheline, oxyphencyclimine, flavoxate, and tricyclic pressants; drugs for blocking nerves ating the bladder and urethra (e.g., vanilloids icin, resiniferatoxin), botulinum-A toxin); or drugs that modulate detrusor contraction strength, ition reflex, detrusor sphincter dyssynergia (e.g., GABAb agonists fen), benzodiazapines). In another embodiment, the drug is selected from those known for the ent of incontinence due to neurologic ter deficiency. Examples of these drugs include α-adrenergic agonists, ens, β-adrenergic agonists, tricyclic antidepressants (imipramine, amitriptyline). In still another embodiment, the drug is selected from those known for facilitating bladder emptying (e.g., α-adrenergic antagonists (phentolamitie) or cholinergics).
In yet another embodiment, the drug is selected from among anticholinergic drugs (e.g., dicyclomine), calcium channel blockers (e.g., verapamil) tropane alkaloids (e.g., atropine, scopolamine), nociceptin/orphanin FQ, and bethanechol (e.g., M3 muscarinic agonist, choline In some ments, an agent that increases the osmotic pressure may be disposed in the water-permeable body or included in the drug formulation or, in some embodiments, the drug itself may act as an osmotic agent. For example, the drug and osmotic agent can be homogeneously mixed or compressed into tablets. As another example, a drug tablet may be disposed near a restraining plug, and an osmotic agent can be arranged next to the drug tablet.
Non-limiting examples of osmotic agents include urea, citric acid, L-tartaric acid, lactose- fructose, dextrose-fructose, sucrose-fructose, mannitol-fructose, sodium chloride, se, lactose-sucrose, potassium chloride, lactose-dextrose, mannitol-dextrose, dextrose-sucrose, mannitol-sucrose, sucrose, mannitol-lactose, dextrose, potassium e, ol, sodium phosphate tribase∙12 H2O, sodium phosphate dibasic∙7 H2O, sodium phosphate dibasic anhydrous, and sodium phosphate monobasic∙H2O.
Use and Applications of the Device The device may be deployed in a body cavity or lumen, and subsequently may release one or more drugs for the treatment of one or more conditions, locally to one or more tissues at the deployment site and/or regionally to other tissues distal from the deployment site. The release may be controlled over an extended period. Thereafter, the device may be removed, resorbed, excreted, or some combination thereof.
In one example, the device is ed into the body by g the drug ry device through a ment instrument and releasing the device from the deployment instrument into the body. In cases in which the device is deployed into a body cavity such as the bladder, the device assumes a retention shape, such as an ed or higher profile shape, once the device s from the deployment instrument into the cavity. An example is illustrated in which shows the device 700 assuming a retention shape as the device exits a deployment instrument 702. The deployment instrument 702 may be any suitable lumen device, such as a catheter, urethral catheter, or cystoscope. The deployment instrument 702 may be a commercially ble device or a device specially adapted for the present drug delivery devices, for example, as described in U.S. Patent Application Publication 2011/0202036 to Boyko et al.
Once inserted into the body, the device releases the drug in a controlled manner. The device may provide extended, continuous, ittent, or periodic release of a desired quantity of drug over a desired, predetermined time period. In embodiments, the device can deliver the desired dose of drug over an extended period, such as 12 hours, 24 hours, 5 days, 7 days, 10 days, 14 days, or 20, 25, 30, 45, 60, or 90 days, or more. In a preferred ment, the device is an intravesical drug delivery device, which releases a therapeutic amount of a drug continuously into urine in the bladder over a selected treatment period ranging from 7 days to 60 days, e.g., from 14 days to 30 days. The rate of delivery and dosage of the drug can be selected depending upon the drug being delivered and the disease or condition being treated.
In embodiments in which the device comprises a drug in a solid form, elution of drug from the device occurs following dissolution of the drug within the device. Bodily fluid enters the device, contacts the drug and solubilizes the drug, and thereafter the dissolved drug exits the device via the microchannels described herein. For example, the drug may be solubilized upon contact with urine in cases in which the device is deployed in the bladder.
Subsequently, the device may be retrieved from the body, such as in cases in which the device is sorbable, non-collapsible, or otherwise needs to be removed.
The device also may be ured to be completely or partially bioresorbable, such that retrieval is unnecessary. In one case, the device is ed or sufficiently degraded that it can be expelled from the bladder during urination. In some embodiments, the device include biodegradable links such that the device can collapse into a shape that permits e through the urethra during urination, as described in U.S. Patent 8,690,840 to Lee et al., which is incorporated herein by reference. The device may not be retrieved or resorbed until some of the drug, or preferably most or the entire drug, has been released. illustrates the deployment of a device 800 into the bladder, n the adult human male anatomy is shown by way of example. A ment instrument 802 may be inserted through the urethra to the bladder, and the device 800 may be passed through the deployment instrument 802, driven by a stylet and/or a flow of lubricant or other fluid, for example, until the device 800 exits into the bladder. Thus, the device is deployed into the bladder of a male or female human patient in need of treatment.
The device may be deployed into the bladder of a t in an independent procedure or in conjunction with another urological or other procedure or surgery, either before, during, or after the other procedure. The device may release one or more drugs that are delivered to local and/or regional tissues for therapy or prophylaxis, either peri-operatively, peratively, or both.
In one embodiment, the drug delivery device, with a self-contained drug payload, is deployed wholly within the bladder to e sustained delivery of at least one drug to the bladder in an amount that is therapeutically ive for the target tissue in need of treatment. It may be the bladder itself or regionally proximate to the bladder. Such al delivery may provide an alternative to systemic administration, which may entail undesirable side effects or result in insufficient bioavailability of the drug. Following in vivo deployment of the device, at least a portion of the payload of drug is ed from the device substantially continually over an extended period, to the urothelium and possibly to nearby tissues, in an amount effective to provide ent or to improve r function in the patient. In a preferred embodiment, the device resides in the bladder releasing the drug over a ermined period, such as two weeks, three weeks, four weeks, a month, or more.
In such cases, the device may be used to treat interstitial cystitis, radiation cystitis, pelvic pain, tive bladder syndrome, bladder cancer, neurogenic bladder, neuropathic or nonneuropathic bladder-sphincter dysfunction, infection, post-surgical pain or other diseases, disorders, and conditions treated with drugs delivered to the bladder. The device may deliver drugs that improve bladder function, such as bladder capacity, compliance, and/or frequency of uninhibited ctions, that reduce pain and discomfort in the bladder or other nearby areas, or that have other effects, or combinations thereof. The bladder-deployed device also may deliver a therapeutically effective amount of one or more drugs to other genitourinary sites within the body, such as other locations within urological or reproductive systems of the body, including one or both of the kidneys, the urethra, one or both of the s, the penis, the , one or both of the seminal vesicles, one or both of the vas deferens, one or both of the ejaculatory ducts, the te, the vagina, the uterus, one or both of the ovaries, or one or both of the fallopian tubes, among others or combinations thereof. For example, the intravesical drug delivery device may be used in the treatment of kidney stones or fibrosis, erectile dysfunction, among other diseases, disorders, and conditions.
In one embodiment, the intravesical drug delivery device is deployed into a bladder to locally deliver lidocaine or another anesthetic agent for management of pain arising from any source, such as a disease or disorder in genitourinary tissues, or pain stemming from any bladder procedure, such as surgery, catheterization, ablation, medical device implantation, or stone or foreign object removal, among others.
In embodiments, the drug delivery device is sterilized, such as after the device is manufactured/assembled and before the device is ed into the patient. In some cases, the device may be sterilized after the device is packaged, such as by subjecting the package to gamma irradiation, electron beam ation, or ethylene oxide gas. Although gamma ation may affect the performance of certain s of the drug delivery devices, materials and configurations can be chosen, as explained herein, to eliminate or substantially neutralize any adverse effects.
In one aspect, a method of administering a drug to a patient includes inserting any of the drug delivery devices bed herein into a lumen or body cavity of a patient; and ting water influx into the reservoir to develop a pressure in the reservoir effective to cause the drug to flow from the reservoir through any preformed through-holes present in the device body and through one or more microchannels formed between the restraining plug and the elastic portion of the device body from (i) the drug reservoir and at least one preformed e port or (ii) the drug reservoir and an opening at the end of the , and out of the device and into the lumen or body . In certain embodiments, the body cavity is the bladder of the patient.
In some particular embodiments, trospium is locally administered into the bladder of a patient for the treatment of neurogenic detrusor overactivity (NDO) resulting from a spinal cord injury (SCI). In some embodiments, the patient is one who has been diagnosed to have traumatic or nontraumatic acral SCI for longer than 6 months and a documented history of NDO.
Such a patient may also need to use an intravesical er (non-indwelling) to empty his or her bladder. In some of these embodiments, the local administration of the trospium into the urinary bladder of the patient is accomplished using one of the drug delivery systems described herein.
In some particular embodiments, the device (containing a payload of trospium, e.g., tablets comprising trospium chloride) is placed into the bladder through an inserter and then the device is removed 30 to 60 days later, such as 42 days later. The device releases the trospium gradually, continuously, during the indwelling time. In some of these embodiments, the device releases trospium at a daily average rate of from about 2 mg/day to about 30 mg/day, for e from about 5 mg/day to about 25 mg/day, such as from about 5 mg/day to about 15 , or about , over the treatment period, e.g., over a 42-day ling time. In some other ments, the trospium may be locally administered into the urinary bladder by other delivery systems known in the art, for example as described in U.S. Patent Application Publication No. 2015/0182516 to Giesing, which is orated herein by reference.
In some particular embodiments, trospium is locally administered into the bladder of a patient for the treatment of thic overactive bladder (iOAB) and urinary incontinence. In some embodiments, the patient is one who has been diagnosed to have symptoms of OAB (frequency/urgency) with urge urinary incontinence or mixed urinary incontinence with a predominant urge component for at least 6 months. In some of these embodiments, the local administration of the trospium into the urinary bladder of the patient is lished using one of the drug delivery systems described . In some particular ments, the device (containing a payload of trospium, e.g., tablets comprising trospium chloride) is placed into the r through an inserter and then the device is removed 30 to 60 days later, such as 42 days later. The device releases the trospium gradually, continuously, during the ling time. In some of these embodiments, the device releases trospium at a daily average rate of from about 2 mg/day to about 30 mg/day, for example from about 5 mg/day to about 25 mg/day, such as from about 5 mg/day to about 15 mg/day, or about 10 mg/day, over the treatment period, e.g., over a 42-day indwelling time. In some other embodiments, the trospium may be locally administered into the urinary bladder by other delivery systems known in the art, for example as described in U.S. Patent Application Publication No. 182516 to Giesing, which is incorporated herein by reference.
The t invention may be further understood with reference to the following nonlimiting Example 1 Prototypes of devices having a central laser-drilled orifice were manufactured and loaded with trospium chloride tablets. One set of the devices included two spacer orifices (i.e., plugs having longitudinal orifices formed therein) at each end, with the second set of devices having two restraining plugs at the ends. Illustrations of the prototypes are shown at FIGS. 11 and 12.
The device of has three drug release apertures: two at the opposing ends and one in the sidewall. The device had a drug reservoir lumen inner diameter of 2.64 mm and a wall thickness of 0.2 mm. The wall had a durometer of 50A. The device of has one release aperture plus two opposing ends capable of providing e upon sufficient osmotic pressure to form hannels. The device had a drug reservoir lumen inner diameter of 2.64 mm and a wall thickness of 0.2 mm. The wall had a ter of 50A.
The devices were placed in containers of deionized water and the amount of trospium chloride ed over time was measured. Results of in vitro tests (five for each prototype design) are shown in the graphs of FIGS. 11 and 12. As can be seen, the restraining plugs achieve a consistent, reproducible release profile, as compared to the less reproducible release profile of the spacer orifice device. The ed difference n the two systems was not predictable.
Example 2 The device illustrated in was manufactured as follows. The device was a dual lumen silicone tube with a laser-machined orifice, parylene C coated silicone elastomer plugs to contain the drug as well as to form one-way valve at each end of the drug compartment in the drug lumen, and white silicone adhesive in the large lumen to hold the plugs in place, a preformed superelastic nitinol wireform housed in the retention frame lumen, and retention lumen ends sealed with translucent silicone ve. The drug was formed as tablets containing trospium chloride (pharmaceutical active ingredient), povidone inylpyrrolidone (PVP)) K29/32 (a binding agent excipient), and polyethylene glycol 8000 (a lubricant excipient). Each device ned 850 mg of trospium chloride. The device is small in size (less than 5 cm on the long axis), flexible, and contoured, in order to minimize potential irritation and inflammation.
The drug reservoir lumen had an inner diameter of 2.64 mm and a wall thickness of 0.41 mm.
The l wire had a thickness of 0.279 mm.
The device body serves as an osmotic pump and provides passive controlled release of the drug when filled with drug while the nitinol wireform provides bladder retention of the system during a treatment period while the system s free-moving in the bladder. The device, as an osmotic pump, delivers the therapeutic agent at a controlled rate by osmosis. The silicone tube wall housing the trospium mini-tablets acts as a semipermeable membrane, and the thickness of the wall can modulate water flux into the system and eventually control the drug release rate. There are multiple drug release channels in the system; one in the middle of the system, and the others are at the ends. The rate of drug delivery is controlled by water permeability of a semipermeable membrane and the osmotic properties of therapeutic and c agent in the lumen. Trospium chloride has a high water solubility and is its own osmotic agent; no additional c agent is ed. This particular device was designed to deliver trospium chloride at a rate of approximately 10 mg/day.
The system was placed in deionized water at 37 ºC, and the rate of release of the um was determined. The in vitro results (average ± SD, n=3) are shown in . As can be seen, the average daily release rate was approximately 10 mg/mL. Thus, it was determined that the system can be ed to provide a desired daily release profile of trospium chloride.
Example 3 Trospium releasing intravesical devices were ctured for in vitro release characterization, according to the parameters of Table 1. The devices were manufactured using one of two types of silicone housing parts. One type (RW) included an annular tube having a wall thickness of 0.2 mm ng the drug reservoir lumen and having a 50A durometer. The other type (TW) included an annular tube having a wall thickness of 0.4 mm bounding the drug reservoir lumen and having a 35A durometer. Both of the types of silicone parts had a drug reservoir lumen inner diameter of 2.64 mm. All of the devices had a 150 µm diameter laserdrilled orifice, which was approximately centered in the sidewall of the silicone part. Systems were assembled using plugs of different lengths. Systems either contained two plugs, one on each end, or one plug with a spacer on the other end of the system that seals that end of the oir (i.e., such that no hannels can form at that end). The drug reservoir lumen of each system was filled with approximately 996 mg of um chloride tablets, with a composition of 95 percent um chloride-polyvinylpyrrolidone (PVP) granules with a 97:3 ratio (percent w/w), and 5 percent polyglycol 8000 PF (PEG 8k) by mass. Trospium chloride acted as both the active agent and osmotic agent to drive the osmotic drug release mechanism. A total of 42 device systems were used for this in vitro stability characterization. All systems were irradiated.
For the RW systems, first-order trospium e kinetics was observed after initial peak release rates of approximately 18 to 24 mg/day by day 7. The TW systems had an initial peak release rate between 10 and 15 mg/day with constant release rates of 10 to 14 mg/day over the next 35 days. The RW systems displayed a higher tive release than the TW systems, but the number of plugs present in the systems and the length of the plugs had no effect on the e rates of the systems.
Type of System Tablet Mass Drug Core Silicone Plug Spacer Length No. (mg)* Length (cm)** Body No. No. 1 1000.6 15.6 2 993.5 15.6 1 1 3 1003.3 15.5 RW 5 4 999.8 15.7 998.3 15.8 2 0 6 989.9 15.5 7 990.9 15.6 8 994.5 15.4 1 1 9 995.3 15.6 993.2 15.5 11 999.8 15.5 2 0 12 992.9 15.5 13 992.7 15.5 14 991.1 15.4 1 1 993.9 15.6 16 996.8 15.7 17 991.3 15.6 2 0 18 986.6 15.7 19 992 15.4 994.5 15.3 1 1 21 1000.6 15.4 22 997.6 15.5 23 990.5 15.3 2 0 24 1000.8 15.5 990.9 15.4 26 1001.3 15.4 1 1 27 992.1 15.4 TW 8 28 1000.9 15.6 29 1002.8 15.6 2 0 1002.2 15.7 31 997.8 15.3 32 994.9 15.5 1 1 33 1000.7 15.5 34 996.7 15.6 998.9 15.5 2 0 36 992.2 15.5 37 - 15 38 - 15 RW 39 - 15 8 2 0 40 - 15 41 - 15.1 TW 42 - 15.1 Table 1: Device ation *The total linear length of the tablets was approximately 14.9 cm when the tablets were serially laid out **Approximate linear length between two spacer surfaces facing the tablets when the system was straightened All irradiated units were used for in vitro release testing. Each unit was placed in a glass jar filled with 300.00 +/- 0.05g degassed deionized water and put in an environmental chamber kept at 37˚C. Samples were taken from each jar at predetermined time points (T= 1, 2, 4, 7, 10, 14, 21, 28, 35, and 42 days). At each time point, release jars were ed 15 times and a 1 mL sample was taken and replaced with 1 mL fresh release media. At days 14 and 28, the release media was fully replaced. Trospium time point samples were analyzed using high-performance liquid chromatography (HPLC) operated by MassLynx.
Trospium chloride e rate (mg/day) at a given time point T(i) was estimated using a backward difference method according to on 1: e rate at T(i) (mg FBE/day) = Q(g)?Q(g?5) (Eq. 1) X(g) ? X(g?5) where M(i) and M(i-1) are cumulative amount released at the current time point T(i) and the previous time point T(i-1), respectively. The cumulative amount of trospium released data seen in was used to create the trospium chloride rate of release profiles seen in FIGS. 18 through 21. The initial drug load was used to estimate the percent amount of um released which can be seen in . The e cumulative percent of trospium released for each configuration type can be seen in Table 2 below.
System Characteristics Average cumulative Percent Released (%) Tubing Plug/Spacer Plug n Media Day 4 Day 21 Day 42 Type configuration Length Type (mm) Avg RSD(%) Avg RSD(%) Avg RSD(%) 1 plug and 1 5 1.64 33.45 38.76 2.81 57.19 4.88 spacer 2 plugs 5 2.36 8.28 38.31 2.62 57.33 2.43 50A 1 plug and 1 8 0.54 124.04 37.42 3.70 56.62 2.82 spacer 2 plug 8 2.41 8.68 38.56 4.83 58.31 4.76 3 DI Water 1 plug and 1 16 1.29 34.07 37.29 2.76 56.17 1.44 spacer 2 plugs 16 1.20 55.14 37.54 1.77 55.75 0.94 1 plug and 1 5 0.59 38.33 23.77 5.97 45.81 2.95 spacer 2 plugs 5 1.09 15.34 24.28 1.30 46.43 0.77 TW 35 A 1 plug and 1 8 0.58 31.10 24.55 2.03 46.71 2.57 spacer 2 plugs 8 0.93 36.62 23.68 4.07 45.62 1.26 1 plug and 1 16 0.48 49.24 23.52 5.14 45.24 3.46 spacer 2 plugs 16 0.58 45.41 22.75 5.11 45.15 2.86 RW 2 plugs 8 4.92 11.95 44.77 1.32 68.10 6.76 TW 2 plugs 8 2.02 15.43 24.82 0.52 49.24 4.25 Table 2: Average percent released at days 4, 21, and 42 for each device uration RW and TW systems with two plugs (see ). First-order trospium release cs were observed after an initial release rate of approximately 18 to 20 mg/day at approximately 7 days since the release experiment started for RW systems with different plug lengths of 5, 8, and 16 mm. After 7 days, a steady decrease in the release rates of the RW systems was observed. At the end of the 42-day experiment, the release rate averaged 5 to 6 mg/day. The initial release rate for TW systems was observed to be approximately 12 to 13 mg/day. After the first 10 days, the release rates remained approximately constant at about 11 to 13 mg/day for the first 35 days.
After the first 35 days, first-order trospium release cs was observed. At the end of the 42- day experiment, the e rates averaged 8 to 9 mg/day. No change in release rate ed with a change in plug length. All RW systems with plugs length of 5, 8, or 16 mm displayed the same release profiles, and all TW s with plugs length of 5, 8, or 16 mm displayed the same release profiles.
System with one plug and one spacer (see ). First-order trospium release kinetics were observed after an initial release rate of approximately 20 to 23 mg/day at approximately 7 days since the e experiment started for RW systems with different plug lengths of 5, 8, and 16 mm. After 7 days, a steady decrease in the release rates of the RW systems was observed. At the end of the 42-day experiment, the release rate averaged 5 to 6 mg/day. The initial release rate for TW systems was observed to be approximately 13 to 15 mg/day. After the first 10 days, the release rates remained approximately constant at about 10 to 13 mg/day for the first 35 days.
After the first 35 days, first-order trospium release kinetics was observed. At the end of the 42- day experiment, the release rates averaged 8 to 9 mg/day. No change in release rate ed with a change in plug length. All RW systems with plugs length of 5, 8, or 16 mm displayed the same release profiles, and all TW systems with plugs length of 5, 8, or 16 mm displayed the same release profiles.
System with one plug and one spacer as compared to two plug systems (see ). All RW systems with plugs length of 5, 8, or 16 mm displayed the same release profiles, and all TW systems with plugs length of 5, 8, or 16 mm displayed the same e profiles. Additionally, the RW and TW systems displayed no change in e rate when comparing the one plug systems versus the two plug 8 mm systems from a lot tested in minipigs. Both a change in plug length and the number of plugs present did not change the release rate of the trospium chloride Systems with 8 mm plugs (see ). First-order trospium release kinetics were ed after an initial e rate of approximately 19 to 24 mg/day at approximately 7 days since the release experiment started for RW s with different plug amounts of 8 mm length.
After 7 days, a steady decrease in the release rates of the RW systems was ed. At the end of the 42-day experiment, the release rate averaged 5 to 6 mg/day. The initial release rate for TW systems was observed to be approximately 10 to 13 mg/day. After the first 10 days, the release rates remained approximately constant at about 10 to 14 mg/day for the first 35 days.
After the first 35 days, first-order trospium release cs was observed. At the end of the 42- day experiment, the release rates averaged 8 to 10 mg/day. No change in release rate occurred with a change in the number of plugs each system contained that were 8 mm in length. All RW systems with plugs length of 8 mm displayed the same release profiles when there was one or two plug in the system, and all TW systems with plugs length of 8 mm displayed the same release es when there were one or two plugs in the system.
In conclusion, osmotic trospium ing devices assembled with 0.2 mm wall thickness (RW) and 0.4 mm wall thickness (TW) loaded with imately 917 mg of trospium chloride were built and an in vitro release experiment was med in 37˚C DI water as the release medium. For RW systems, first-order trospium release kinetics were observed after an initial release rate of approximately 18 to 24 mg/day at approximately 7 days after the release experiment d. The initial e rate for the TW systems was approximately 10 to 15 mg/day. For the TW systems, the release rate remained approximately constant at about 10 to 14 mg/day for the first 28 days. After the first 35 days, first-order trospium release kinetics were observed. Therefore, RW systems had a high initial peak release rate and higher cumulative release of the overall drug load by the end of the experiment. TW systems had a more constant release rate for the first 35 days and a lower cumulative release of the overall drug load. There was no change in the release rate profiles with a change in the number of plugs present or the length of the plugs. All the RW systems displayed approximately the same release rate, cumulative release, and percent release. All the TW systems yed approximately the same e rate, cumulative release, and percent release.
Example 4 Trospium releasing intravesical devices with drug release opening(s) were manufactured for in vitro release testing. Dual lumen silicone tubes were used to construct the systems. The small lumen contained a bi-oval shape wireform and the large lumen was filled with trospium mini-tablets having a composition (percent w/w) of 92 percent trospium chloride, 3 percent PVP, and 5 percent PEG 8K. The amount of trospium chloride loaded in each system was approximately 910 to 920 mg.
Four punched hole configuration. FIGS. 9A-9B show a configuration where four d holes are present, two punched holes in the sidewall of the housing near each end of the drug core. The holes were positioned over parylene C coated silicone restraining plugs with a length of 5 mm and outer er (OD) of 2.77 mm. Silicone adhesive behind the restraining plugs was used to fix the ining plugs in place and the ve sealed the ends of the lumen. A bi-oval shaped wireform was ed into the small lumen of the tube, and silicone adhesive was applied into the small lumen to fix the wireform in place and allowed to cure for approximately 24 hours, after which time the ends were trimmed to 5 mm from the end of the restraining plugs. The silicone restraining plugs were oversized; the inner diameter of the silicone tube was 2.64 mm while the outer diameter of the silicone restraining plugs was 2.77 mm. The parylene coating on the ining plug was used to prevent gamma irradiation induced adhesion at the ne-to-silicone interface after gamma irradiation was used for product sterilization. The punched holes were placed at 2 to 3 mm from each end of the drug core. The punched holes over the oversized restraining plugs were designed to serve as drug release s as osmotic pressure inside the drug chamber is built up.
The location and the number of holes can vary depending on how many and where the restraining plugs are located along the length of the tube. For example, if only one restraining plug and two punched holes are present in the middle of the tube, there will be two drug release openings in the middle of the tube.
Two slit g configuration. FIGS. 10A-10B show a configuration where two slits are present in the device, one slit in the sidewall of the housing near each end of the drug core.
Parylene C coated ne restraining plugs with a length of 5 mm and outer diameter of 2.77 mm were inserted into the tube and then the slits were created by razor blade. The razor blade passed h the tube wall and penetrated partially into the restraining plug, so silicone material from the wall was not removed, in contrast to punched holes where wall material is removed. Silicone adhesive behind the restraining plugs was used to fix the restraining plugs in place and the ve sealed the ends of the lumen. The slits were placed at 2 to 3 mm from each end of the drug core. A l shape wireform was inserted into the small lumen of the tube, and silicone adhesive was applied into the small lumen to fix the wireform in place and allowed to cure for approximately 24 hours after which time the ends were trimmed to 5 mm from the end of the restraining plugs. The silicone restraining plugs were oversized; the inner diameter of the silicone tube was 2.64 mm while the outer diameter of the ne restraining plugs was 2.77 mm. The parylene coating on the restraining plug was used to t gamma irradiation induced adhesion at the silicone-to-silicone ace after gamma irradiation was used for product sterilization. A small piece of paper was inserted into each slit to prevent possible adherence and closure of the wall during the irradiation, and then was removed afterward irradiation. The slits over the oversized restraining plugs were designed to serve as drug e outlets as osmotic pressure inside the drug chamber is built up.
The location and the number of slits can vary depending on how many and where restraining plugs are located along the length of the tube. For example, if only one restraining plug is present in the middle of the tube, there can be one slit in the middle of the tube.
Three opening system (one laser-drilled orifice and two . FIGS. 2 and 3A show a three opening system having a laser-drilled aperture with a 150 micron diameter in the middle of the tube, and two plugs (see FIGS. 3B and 3C), which had the outer diameter of 2.77 mm and the length of 8 mm. The plugs were made of silicone and coated with ne C, and each plug included a bevel at one end (see FIGS. 3A-3C). Silicone adhesive was applied in the region created by the bevel end and the large lumen to fix the plugs in place but the adhesive did not seal the ends of the lumen. FIGS. 3B and 3C shows one end of the three opening system and the plug is shown. FIGS. 1C and 1D show the diagram of such one-way valve; each plug, oversized in the large lumen, forms one-way valve once osmotic pressure in the large lumen is built up.
Unlike the punched holes over zed restraining plugs (FIGS. 9A-9B) and the slits over zed restraining plugs (FIGS. 10A-10B) and the plugs (FIGS. 1C, 1D, 3B, 3C), the laser-drilled hole is an re with a pre-defined opening, which is present regardless of the presence of osmotic pressure in the drug reservoir (i.e., the large lumen or drug compartment lumen).
In vitro release testing. Six types of systems were tested for in vitro e, according to the parameters in Table 3. The shapes of all types of systems were bi-oval. However, the number and configuration of drug release openings, silicone tube wall thickness (RW or TW), and silicone tube hardness (50A and 35A) differed depending on system type. All of the systems were gamma irradiated (25-40 kGy) before being tested for in vitro release.
Type System Silicone tube 1 Four opening system with four punched holes and RW tube (as in FIGS. 9A-9B) r wall (RW) silicone 2 Two opening system with two slits and RW tube (as in tube with a large lumen with FIGS. 10A-10B) 2.64 mm ID and 0.20 mm 3 Three opening system with a laser-drilled orifice and two wall, and 50A durometer plugs and RW tube (as in FIGS. 2-3) 4 Four opening system with four punched holes and TW tube (as in FIGS. 9A-9B) Thick wall (TW) silicone tube Two opening system with two slits and TW tube (as in with a large lumen with 2.64 FIGS. 10A-10B) mm ID and 0.41 mm wall, and 6 Three opening system with a laser-drilled orifice and two 35A durometer plugs and TW tube (as in FIGS. 2-3) Table 3: List of tested systems in in vitro release In vitro e with 0.20 mm wall (RW) tube. The systems were placed in 300 grams of deionized water at 37°C, and time point samples were collected at pre-determined time points to construct in vitro release profiles. FIGS. 14 and 15 show trospium chloride release rates and tive amount ed over time for Type 1, 2, and 3 in Table 3. No noticeable difference was observed in the drug e characteristics between two opening systems (with slits) and four opening systems (with d holes), which supports osmotically controlled drug release.
However, the three g system, which has a pre-defined laser-drilled re and two plugs, showed higher overall cumulative release amount compared with two opening systems and four opening systems.
In vitro release with 0.41 mm wall (TW) tube. The systems were placed in 300 grams of deionized water at 37°C, and time point samples were collected at termined time points to construct in vitro release profiles. FIGS. 16 and 17 show trospium chloride release rates and cumulative amount released over time for Type 4, 5, and 6 in Table 3. No noticeable difference was observed in the drug release characteristics between two opening systems (with slits) and four opening systems (with punched holes), which supports osmotically controlled drug release. r, three opening system, which has a pre-defined laser-drilled aperture and two plugs, showed higher overall cumulative release amount compared with two opening systems and four opening systems.
Example 5 Devices were manufactured to compare a system having two end restraining plugs and no sidewall orifice (such as disclosed in U.S. Patent Application Publication 2016/0008271 to Lee) with a system having med ports in the sidewall adjacent restraining plugs and no sidewall orifice (such as illustrated in . The device ters are given below in Table 4.
The devices were immersed in deionized water and the release rate of the drug was measured over time. The results are illustrated in , which demonstrates that the system having the punched holes with adjacent ining plugs to form the microchannels therebetween produces a similar release profile over the 84 day in vitro release test as compared to the prior plug only system. Indeed, the system having punched holes with restraining plugs showed a smoother release profile as compared to the plug only .
Sample Drug Constituent Device Constituent IVR Conditions 100.00±0.05g of DI water Emerson Tablets, 2.16mm ID x for the first 14 days and Lot CU06-050, 0.4mm wall then increased to 1 95% Tros/PVP Gran (97:3), thickness, Thick ±0.05g of DI water % PEG8K, Wall, 35A, plugs no for 84 days. Stored at 2.16mm OD orifice 37oC. 2.16mm ID x 0.4mm wall thickness, 300.00±0.05g of DI water thick wall, 35A, 2 for 84 days. Stored at 4 d holes of 37oC. 0.76 mm diameter each, no orifice Table 4: Device ters for Example 5 Publications cited herein and the materials for which they are cited are specifically incorporated by reference. Modifications and variations of the methods and devices described herein will be obvious to those skilled in the art from the foregoing detailed description. Such modifications and variations are intended to come within the scope of the appended claims.
The ing numbered paragraphs define particular aspects of the present invention: 1. A drug delivery device comprising: a body that comprises a wall bounding a reservoir defined within the body, the wall having at least one preformed through-hole ed therein and comprising a water-permeable portion, the body comprising an elastic portion; a drug formulation which comprises a drug, the drug ation being ed within the reservoir; and at least one restraining plug closing off an opening of the body and ting the elastic portion of the body, the opening being in fluid communication with the reservoir, wherein the water-permeable portion of the wall is configured to permit water to enter the drug delivery device and t the drug formulation located in the reservoir, wherein release of the drug from the device is controlled by (i) release of the drug through the at least one preformed through-hole in the wall, and (ii) release of the drug through the transient formation of one or more hannels between the elastic portion of the body and the at least one restraining plug, extending to the opening, upon the generation within the reservoir of a hydrostatic pressure effective to form the one or more microchannels. 2. The drug ry device of paragraph 1, wherein release of the drug through the at least one preformed through-hole is osmotically driven. 3. The drug delivery device of paragraph 1, wherein: the at least one restraining plug has an outer diameter, the elastic portion of the body defines an opening having an inner diameter, and the outer diameter of the restraining plug exceeds the inner diameter of the elastic portion of the body by at least 3 percent. 4. The drug delivery device of paragraph 3, n the outer er of the restraining plug exceeds the inner diameter of the elastic portion of the body by at least 5 percent, at least 10 percent, at least 15 percent, at least 20 percent, or at least 25 percent.
. The drug delivery device of paragraph 1, wherein the body further comprises an inelastic portion. 6. The drug delivery device of paragraph 1, n the at least one restraining plug is secured within the opening in the elastic n of the body with an adhesive. 7. The drug delivery device of paragraph 1, wherein the drug formulation is in a solid form. 8. The drug delivery device of paragraph 7, n the device is ured to permit, in vivo, water to diffuse through the water-permeable n of the wall and into the reservoir to solubilize the solid drug formulation. 9. The drug ry device of paragraph 1, wherein the drug comprises trospium or another antimuscarinic agent.
. The drug delivery device of paragraph 1, further comprising an osmotic agent. 11. The drug delivery device of paragraph 10, wherein the osmotic agent is a component of the drug formulation. 12. The drug delivery device of paragraph 1, wherein the at least one restraining plug is substantially cylindrical. 13. The drug delivery device of paragraph 1, n the at least one restraining plug comprises a wedged, tapered, angled, or rounded surface. 14. The drug delivery device of paragraph 1, wherein the Shore durometer of the elastic portion of the body is from about 40A to about 60A, and the Shore durometer of the at least one restraining plug is from about 70A to about 100A.
. The drug delivery device of paragraph 1, n the Shore durometer of the elastic portion of the body is from about 45A to about 55A, and the Shore ter of the at least one restraining plug is from about 75A to about 85A. 16. The drug delivery device of paragraph 1, wherein the Shore durometer of the elastic portion of the body is about 50A, and the Shore durometer of the at least one restraining plug is about 80A. 17. The drug delivery device of paragraph 1, wherein the device is elastically able between a relatively straightened shape suitable for insertion through a lumen into a body cavity of a patient and a retention shape suited to retain the device within the body cavity. 18. The drug delivery device of paragraph 1, wherein the body is formed from an elastomeric tube. 19. The drug delivery device of paragraph 1, wherein the elastic portion of the body is formed from a water-permeable material.
. The drug delivery device of paragraph 1, wherein the one or more microchannels are not preformed es. 21. The drug delivery device of aph 1, wherein the at least one restraining plug has a parylene coating. 22. A method of administering a drug to a patient, comprising: inserting the drug delivery device of any one of paragraphs 1 to 21 into a lumen or body cavity of a patient; and permitting water influx into the reservoir to develop a re in the reservoir ive to cause the drug to flow from the reservoir through at least one of the preformed through-hole and the one or more microchannels and out of the device and into the lumen or body cavity. 23. The method of paragraph 22, wherein the body cavity is the bladder of the t. 24. A drug delivery device comprising: a tubular body that comprises a wall bounding a reservoir defined within the body, the wall comprising a water-permeable portion and an elastic portion having at least one preformed release port disposed therein; a drug formulation which comprises a drug, the drug formulation being disposed within the reservoir, wherein the water-permeable portion of the wall permits water to enter the drug ry device and contact the drug formulation located in the reservoir; and at least one restraining plug d within the reservoir in contact with the elastic n of the body and adjacent the at least one preformed release port, such that the at least one restraining plug controls release of the drug from the device, via the at least one preformed release port, by the transient formation of one or more microchannels n the elastic portion of the body and the at least one restraining plug, extending to the at least one med release port, upon the generation of a hydrostatic pressure within the oir effective to form the one or more microchannels.
. The drug delivery device of paragraph 24, wherein the at least one preformed release port comprises a through-hole or a slit disposed in the wall. 26. The drug delivery device of paragraph 24, wherein: the at least one restraining plug has an outer diameter, the elastic n of the body has an inner diameter, and the outer diameter of the restraining plug exceeds the inner diameter of the elastic portion of the body by at least 3 percent. 27. The drug delivery device of paragraph 24, wherein the outer diameter of the ining plug exceeds the inner diameter of the elastic portion of the body by at least 5 percent, at least 10 percent, at least 15 percent, at least 20 percent, or at least 25 percent. 28. The drug ry device of paragraph 24, wherein the body further ses an inelastic portion. 29. The drug delivery device of paragraph 24, wherein the at least one restraining plug is secured within the elastic portion of the body with an adhesive.
. The drug delivery device of paragraph 24, wherein the drug formulation is in a solid form. 31. The drug delivery device of aph 30, wherein the device is ured to permit, in vivo, water to diffuse through the water-permeable portion of the wall and into the reservoir to solubilize the solid drug formulation. 32. The drug delivery device of paragraph 24, wherein the drug comprises trospium or another scarinic agent. 33. The drug delivery device of paragraph 24, further comprising an osmotic agent. 34. The drug delivery device of paragraph 33, wherein the osmotic agent is a component of the drug formulation.
. The drug delivery device of paragraph 24, wherein the at least one restraining plug is substantially cylindrical. 36. The drug delivery device of paragraph 24, wherein the Shore durometer of the elastic portion of the body is from about 40A to about 60A, and the Shore durometer of the at least one restraining plug is from about 70A to about 100A. 37. The drug delivery device of paragraph 24, wherein the Shore durometer of the c portion of the body is from about 45A to about 55A, and the Shore ter of the at least one restraining plug is from about 75A to about 85A. 38. The drug delivery device of aph 24, wherein the Shore durometer of the elastic portion of the body is about 50A, and the Shore durometer of the at least one ining plug is about 80A. 39. The drug ry device of paragraph 24, wherein the device is elastically deformable between a relatively straightened shape suitable for insertion through a lumen into a body cavity of a patient and a retention shape suited to retain the device within the body cavity. 40. The drug delivery device of paragraph 24, wherein the elastic portion of the body is formed from a water-permeable material. 41. The drug delivery device of aph 24, wherein the one or more microchannels are not preformed orifices. 42. The drug delivery device of paragraph 24, wherein the at least one restraining plug has a parylene coating. 43. The drug delivery device of paragraph 24, further comprising at least one preformed h-hole disposed in the wall of the body, wherein release of the drug from the device is further controlled by release of the drug through the at least one preformed through-hole in the wall. 44. The drug ry device of paragraph 43, n release of the drug through the at least one med through-hole is osmotically driven. 45. A method of administering a drug to a patient, comprising: inserting the drug delivery device of any one of paragraphs 24 to 44 into a lumen or body cavity of a patient; and permitting water influx into the reservoir to develop a hydrostatic pressure in the reservoir effective to form one or more hannels between the elastic portion of the body and the at least one restraining plug, extending to the at least one preformed release port, thereby causing the drug to flow from the reservoir, h the microchannels, and out of the device and into the lumen or body cavity. 46. The method of paragraph 45, wherein the body cavity is the bladder of the patient. 47. A method of treating a patient in need of treatment for neurogenic detrusor tivity (NDO) resulting from a spinal cord injury (SCI), the method comprising: locally administering an effective amount of trospium into the urinary r of the t continuously over a treatment period of 30 to 60 days. 48. The method of paragraph 47, wherein the locally administering an effective amount of trospium comprises releasing the trospium into urine in the bladder from a drug delivery device located within the t’s bladder. 49. The method of paragraph 47, wherein the treatment period is 42 days. 50. The method of paragraph 47, wherein the trospium is released into the bladder at a daily average rate of from about 2 mg/day to about 30 mg/day over the treatment period. 51. The method of paragraph 47, wherein the trospium is released into the bladder at a daily average rate of from about 5 mg/day to about 25 mg/day over the treatment period. 52. The method of aph 47, wherein the trospium is released into the r at a daily e rate of from about 5 mg/day to about 15 mg/day over the treatment period. 53. The method of paragraph 47, wherein the trospium is released into the bladder at a daily average rate of about 10 mg/day over the treatment period. 54. A method of treating a patient in need of treatment for idiopathic overactive bladder (iOAB) and urinary incontinence, the method comprising: locally administering an effective amount of trospium into the urinary bladder of the patient continuously over a treatment period of 30 to 60 days. 55. The method of paragraph 54, wherein the locally stering an effective amount of trospium comprises releasing the trospium into urine urine in the bladder from a drug delivery device located within the patient’s r. 56. The method of aph 54, wherein the ent period is 42 days. 57. The method of paragraph 54, wherein the trospium is released into the bladder at a daily e rate of from about 2 mg/day to about 30 mg/day over the treatment period. 58. The method of paragraph 54, wherein the trospium is released into the bladder at a daily average rate of from about 5 mg/day to about 25 mg/day over the treatment period. 59. The method of paragraph 54, wherein the trospium is released into the bladder at a daily average rate of from about 5 mg/day to about 15 mg/day over the treatment period. 60. The method of paragraph 54, wherein the trospium is released into the bladder at a daily average rate of about 10 mg/day over the treatment period.
Claims (7)
1. A use of trospium in the manufacture of a medicament for treating a patient in need of treatment for thic overactive r (iOAB) and urinary incontinence, wherein the tropsium is to be locally administered into the urinary bladder of the patient continuously over a treatment period of 30 to 60 days.
2. The use of claim 1, wherein the trospium is to be locally administered into urine in the bladder from a drug delivery device located within the patient’s bladder.
3. The use of claim 1, wherein the treatment period is 42 days.
4. The use of claim 1, wherein the trospium is to be released into the bladder at a daily average rate of from about 2 mg/day to about 30 mg/day over the treatment period.
5. The use of claim 1, wherein the um is to be released into the bladder at a daily average rate of from about 5 mg/day to about 25 mg/day over the treatment .
6. The use of claim 1, wherein the um is to be released into the bladder at a daily average rate of from about 5 mg/day to about 15 mg/day over the treatment period.
7. The use of claim 1, wherein the trospium is to be released into the bladder at a daily average rate of about 10 mg/day over the treatment period. W0 44738 PCT/U
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US62/453,333 | 2017-02-01 | ||
US62/480,744 | 2017-04-03 |
Publications (1)
Publication Number | Publication Date |
---|---|
NZ796300A true NZ796300A (en) | 2023-01-27 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10517816B2 (en) | Drug delivery devices and methods for drug delivery | |
US20210275789A1 (en) | Drug delivery devices and methods for drug delivery | |
US10137287B2 (en) | Drug delivery devices and methods for controlled drug release through device orifice | |
AU2022241586A1 (en) | Drug delivery devices and methods | |
NZ796300A (en) | In vivo drug delivery devices and methods for drug delivery | |
RU2809797C2 (en) | Method of treating a patient with idiopathic overactive bladder and urinary incontinence (options) | |
NZ796299A (en) | In vivo drug delivery devices and methods for drug delivery | |
NZ796292A (en) | In vivo drug delivery devices and methods for drug delivery | |
BR112019015812B1 (en) | DRUG DISTRIBUTION DEVICE | |
WO2017151983A1 (en) | Osmotic drug delivery devices and methods of making osmotic drug delivery devices | |
BR112015022427B1 (en) | DRUG RELEASE DEVICE |