MXPA06009041A - Method for making a needle-free jet injection drug delivery device - Google Patents
Method for making a needle-free jet injection drug delivery deviceInfo
- Publication number
- MXPA06009041A MXPA06009041A MXPA/A/2006/009041A MXPA06009041A MXPA06009041A MX PA06009041 A MXPA06009041 A MX PA06009041A MX PA06009041 A MXPA06009041 A MX PA06009041A MX PA06009041 A MXPA06009041 A MX PA06009041A
- Authority
- MX
- Mexico
- Prior art keywords
- drug
- injection
- delivery device
- drug delivery
- further characterized
- Prior art date
Links
- 239000007924 injection Substances 0.000 title claims abstract description 161
- 238000002347 injection Methods 0.000 title claims abstract description 149
- 229940089114 Drug Delivery Device Drugs 0.000 title claims abstract description 97
- 239000003814 drug Substances 0.000 claims abstract description 248
- 229940079593 drugs Drugs 0.000 claims abstract description 240
- 210000001519 tissues Anatomy 0.000 claims abstract description 64
- 230000035515 penetration Effects 0.000 claims abstract description 25
- 239000000463 material Substances 0.000 claims description 15
- 230000003213 activating Effects 0.000 claims description 6
- 238000005553 drilling Methods 0.000 claims description 6
- 238000000338 in vitro Methods 0.000 claims description 6
- 229910052751 metal Inorganic materials 0.000 claims description 5
- 239000002184 metal Substances 0.000 claims description 5
- 239000000919 ceramic Substances 0.000 claims description 4
- 229910001092 metal group alloy Inorganic materials 0.000 claims description 4
- 229920001169 thermoplastic Polymers 0.000 claims description 4
- 239000004416 thermosoftening plastic Substances 0.000 claims description 4
- 238000003754 machining Methods 0.000 claims description 3
- 238000000465 moulding Methods 0.000 claims description 3
- 150000002739 metals Chemical class 0.000 claims description 2
- 210000001508 Eye Anatomy 0.000 description 48
- 239000000203 mixture Substances 0.000 description 24
- 239000003795 chemical substances by application Substances 0.000 description 23
- -1 germicides Substances 0.000 description 18
- 201000010099 disease Diseases 0.000 description 17
- 238000009472 formulation Methods 0.000 description 14
- 238000004519 manufacturing process Methods 0.000 description 14
- 230000004913 activation Effects 0.000 description 12
- 206010022114 Injury Diseases 0.000 description 11
- 238000005516 engineering process Methods 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- 210000000214 Mouth Anatomy 0.000 description 8
- 210000003491 Skin Anatomy 0.000 description 8
- 208000002193 Pain Diseases 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 7
- 230000001225 therapeutic Effects 0.000 description 7
- 229940012356 Eye Drops Drugs 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000003889 eye drop Substances 0.000 description 6
- 235000018102 proteins Nutrition 0.000 description 6
- 102000004169 proteins and genes Human genes 0.000 description 6
- 108090000623 proteins and genes Proteins 0.000 description 6
- 230000002500 effect on skin Effects 0.000 description 5
- 239000003112 inhibitor Substances 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 238000001746 injection moulding Methods 0.000 description 5
- 238000011068 load Methods 0.000 description 5
- 238000007920 subcutaneous administration Methods 0.000 description 5
- 238000002560 therapeutic procedure Methods 0.000 description 5
- JYGXADMDTFJGBT-VWUMJDOOSA-N Cortisol Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 4
- CGIGDMFJXJATDK-UHFFFAOYSA-N Indometacin 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 4
- 241001465754 Metazoa Species 0.000 description 4
- 210000001747 Pupil Anatomy 0.000 description 4
- 210000003786 Sclera Anatomy 0.000 description 4
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N Theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 4
- 210000004027 cells Anatomy 0.000 description 4
- 239000006185 dispersion Substances 0.000 description 4
- 230000035558 fertility Effects 0.000 description 4
- 239000007943 implant Substances 0.000 description 4
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 4
- 229910052710 silicon Inorganic materials 0.000 description 4
- 239000010703 silicon Substances 0.000 description 4
- 235000012431 wafers Nutrition 0.000 description 4
- 229940088597 Hormone Drugs 0.000 description 3
- 229920002521 Macromolecule Polymers 0.000 description 3
- 208000002780 Macular Degeneration Diseases 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- 210000001331 Nose Anatomy 0.000 description 3
- 206010033372 Pain and discomfort Diseases 0.000 description 3
- 102100015249 VEGFA Human genes 0.000 description 3
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 3
- 239000003708 ampul Substances 0.000 description 3
- 230000001028 anti-proliferant Effects 0.000 description 3
- 238000010276 construction Methods 0.000 description 3
- 230000000881 depressing Effects 0.000 description 3
- 239000003102 growth factor Substances 0.000 description 3
- 239000005556 hormone Substances 0.000 description 3
- 229960000890 hydrocortisone Drugs 0.000 description 3
- 230000001965 increased Effects 0.000 description 3
- 238000001802 infusion Methods 0.000 description 3
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 3
- 238000005457 optimization Methods 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 239000004033 plastic Substances 0.000 description 3
- 229920003023 plastic Polymers 0.000 description 3
- 230000035485 pulse pressure Effects 0.000 description 3
- 230000037390 scarring Effects 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 230000002537 thrombolytic Effects 0.000 description 3
- CFCUWKMKBJTWLW-BGLFSJPPSA-N (2S,3S)-2-[(2S,4R,5R,6R)-4-[(2S,4R,5R,6R)-4-[(2S,4S,5R,6R)-4,5-dihydroxy-4,6-dimethyloxan-2-yl]oxy-5-hydroxy-6-methyloxan-2-yl]oxy-5-hydroxy-6-methyloxan-2-yl]oxy-3-[(1S,3S,4R)-3,4-dihydroxy-1-methoxy-2-oxopentyl]-6-[(2S,4R,5S,6R)-4-[(2S,4R,5S,6R)-4,5-dih Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BGLFSJPPSA-N 0.000 description 2
- WTDRDQBEARUVNC-LURJTMIESA-N 3-hydroxy-L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 description 2
- XRZWVSXEDRYQGC-UHFFFAOYSA-N 4-cyclohexylpyrrolidin-1-ium-2-carboxylate Chemical compound C1NC(C(=O)O)CC1C1CCCCC1 XRZWVSXEDRYQGC-UHFFFAOYSA-N 0.000 description 2
- 206010064930 Age-related macular degeneration Diseases 0.000 description 2
- 229960001230 Asparagine Drugs 0.000 description 2
- UREBDLICKHMUKA-DVTGEIKXSA-N Betamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-DVTGEIKXSA-N 0.000 description 2
- 210000004369 Blood Anatomy 0.000 description 2
- ZAIPMKNFIOOWCQ-UEKVPHQBSA-N Cefalexin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CC=CC=C1 ZAIPMKNFIOOWCQ-UEKVPHQBSA-N 0.000 description 2
- 208000005590 Choroidal Neovascularization Diseases 0.000 description 2
- 206010060823 Choroidal neovascularisation Diseases 0.000 description 2
- PTOAARAWEBMLNO-KVQBGUIXSA-N Cladribine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 PTOAARAWEBMLNO-KVQBGUIXSA-N 0.000 description 2
- IAKHMKGGTNLKSZ-INIZCTEOSA-N Colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 description 2
- 229940039227 DIAGNOSTIC AGENTS Drugs 0.000 description 2
- 229960003957 Dexamethasone Drugs 0.000 description 2
- UREBDLICKHMUKA-CXSFZGCWSA-N Dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 2
- 206010012689 Diabetic retinopathy Diseases 0.000 description 2
- 229940110715 ENZYMES FOR TREATMENT OF WOUNDS AND ULCERS Drugs 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 229940114721 Enzymes FOR DISORDERS OF THE MUSCULO-SKELETAL SYSTEM Drugs 0.000 description 2
- 229940093738 Enzymes for ALIMENTARY TRACT AND METABOLISM Drugs 0.000 description 2
- 108050007372 Fibroblast growth factor family Proteins 0.000 description 2
- 102000018233 Fibroblast growth factor family Human genes 0.000 description 2
- 108010084340 Gonadotropin-Releasing Hormone Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- ZFGMDIBRIDKWMY-PASTXAENSA-N Heparin Chemical compound CC(O)=N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O[C@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@@H](O[C@@H]3[C@@H](OC(O)[C@H](OS(O)(=O)=O)[C@H]3O)C(O)=O)O[C@@H]2O)CS(O)(=O)=O)[C@H](O)[C@H]1O ZFGMDIBRIDKWMY-PASTXAENSA-N 0.000 description 2
- 108010000521 Human Growth Hormone Proteins 0.000 description 2
- 102000002265 Human Growth Hormone Human genes 0.000 description 2
- 239000000854 Human Growth Hormone Substances 0.000 description 2
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-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
- 229960000905 Indomethacin Drugs 0.000 description 2
- 102000004877 Insulin Human genes 0.000 description 2
- 108090001061 Insulin Proteins 0.000 description 2
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 2
- 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 2
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Nitrumon Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 2
- VIKNJXKGJWUCNN-XGXHKTLJSA-N Norethisterone Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 VIKNJXKGJWUCNN-XGXHKTLJSA-N 0.000 description 2
- 229940074730 OPHTHAMOLOGIC DIAGNOSTIC AGENTS Drugs 0.000 description 2
- 229960003418 Phenoxybenzamine Drugs 0.000 description 2
- QZVCTJOXCFMACW-UHFFFAOYSA-N Phenoxybenzamine Chemical compound C=1C=CC=CC=1CN(CCCl)C(C)COC1=CC=CC=C1 QZVCTJOXCFMACW-UHFFFAOYSA-N 0.000 description 2
- 229960003171 Plicamycin Drugs 0.000 description 2
- OIGNJSKKLXVSLS-VWUMJDOOSA-N Prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 2
- WIKYUJGCLQQFNW-UHFFFAOYSA-N Prochlorperazine Chemical compound C1CN(C)CCN1CCCN1C2=CC(Cl)=CC=C2SC2=CC=CC=C21 WIKYUJGCLQQFNW-UHFFFAOYSA-N 0.000 description 2
- 108010057464 Prolactin Proteins 0.000 description 2
- 229940097325 Prolactin Drugs 0.000 description 2
- 102000003946 Prolactin Human genes 0.000 description 2
- 210000001525 Retina Anatomy 0.000 description 2
- QFJCIRLUMZQUOT-HPLJOQBZSA-N Sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 2
- 229960005202 Streptokinase Drugs 0.000 description 2
- 108010023197 Streptokinase Proteins 0.000 description 2
- MLKXDPUZXIRXEP-MFOYZWKCSA-N Sulindac Chemical compound CC1=C(CC(O)=O)C2=CC(F)=CC=C2\C1=C/C1=CC=C(S(C)=O)C=C1 MLKXDPUZXIRXEP-MFOYZWKCSA-N 0.000 description 2
- 229960000894 Sulindac Drugs 0.000 description 2
- 229960001967 Tacrolimus Drugs 0.000 description 2
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 description 2
- 229960000278 Theophylline Drugs 0.000 description 2
- UPSPUYADGBWSHF-UHFFFAOYSA-N Tolmetin Chemical compound C1=CC(C)=CC=C1C(=O)C1=CC=C(CC(O)=O)N1C UPSPUYADGBWSHF-UHFFFAOYSA-N 0.000 description 2
- GFNANZIMVAIWHM-OBYCQNJPSA-N Triamcinolone Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 GFNANZIMVAIWHM-OBYCQNJPSA-N 0.000 description 2
- RXPRRQLKFXBCSJ-GIVPXCGWSA-N Vincamine Chemical compound C1=CC=C2C(CCN3CCC4)=C5[C@@H]3[C@]4(CC)C[C@](O)(C(=O)OC)N5C2=C1 RXPRRQLKFXBCSJ-GIVPXCGWSA-N 0.000 description 2
- MCMNRKCIXSYSNV-UHFFFAOYSA-N ZrO2 Chemical compound O=[Zr]=O MCMNRKCIXSYSNV-UHFFFAOYSA-N 0.000 description 2
- 229960001138 acetylsalicylic acid Drugs 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000003110 anti-inflammatory Effects 0.000 description 2
- 239000002260 anti-inflammatory agent Substances 0.000 description 2
- 230000002927 anti-mitotic Effects 0.000 description 2
- 229940019336 antithrombotic Enzymes Drugs 0.000 description 2
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 2
- 229960002537 betamethasone Drugs 0.000 description 2
- 230000003115 biocidal Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 108010006025 bovine growth hormone Proteins 0.000 description 2
- 229960003525 cefalexin Drugs 0.000 description 2
- 230000001413 cellular Effects 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 238000002485 combustion reaction Methods 0.000 description 2
- 238000004891 communication Methods 0.000 description 2
- 239000004035 construction material Substances 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 239000000032 diagnostic agent Substances 0.000 description 2
- 235000015872 dietary supplement Nutrition 0.000 description 2
- 238000009792 diffusion process Methods 0.000 description 2
- 238000007599 discharging Methods 0.000 description 2
- 238000004880 explosion Methods 0.000 description 2
- 239000002360 explosive Substances 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 239000000122 growth hormone Substances 0.000 description 2
- 229940020899 hematological Enzymes Drugs 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- 230000003054 hormonal Effects 0.000 description 2
- 229960001680 ibuprofen Drugs 0.000 description 2
- 229960004801 imipramine Drugs 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 229960004502 levodopa Drugs 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-L maleate(2-) Chemical compound [O-]C(=O)\C=C/C([O-])=O VZCYOOQTPOCHFL-UPHRSURJSA-L 0.000 description 2
- 229960000485 methotrexate Drugs 0.000 description 2
- 238000000520 microinjection Methods 0.000 description 2
- 229960000993 norethisterone Drugs 0.000 description 2
- RZVAJINKPMORJF-UHFFFAOYSA-N p-acetaminophenol Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 2
- 230000036961 partial Effects 0.000 description 2
- 229940083249 peripheral vasodilators Enzymes Drugs 0.000 description 2
- 238000002428 photodynamic therapy Methods 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 229960005205 prednisolone Drugs 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 229960003111 prochlorperazine Drugs 0.000 description 2
- 229960002930 sirolimus Drugs 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 230000001954 sterilising Effects 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- WYWHKKSPHMUBEB-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 2
- 229960001017 tolmetin Drugs 0.000 description 2
- 229960005294 triamcinolone Drugs 0.000 description 2
- 230000001960 triggered Effects 0.000 description 2
- PMATZTZNYRCHOR-CGLBZJNRSA-N (3S,6S,9S,12R,15S,18S,21S,24S,30S,33S)-30-ethyl-33-[(E,1R,2R)-1-hydroxy-2-methylhex-4-enyl]-1,4,7,10,12,15,19,25,28-nonamethyl-6,9,18,24-tetrakis(2-methylpropyl)-3,21-di(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacontane-2,5,8,11,14,17 Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 1
- BFSMWENDZZIWPW-UHFFFAOYSA-N (4-amino-4-oxo-3,3-diphenylbutyl)-methyl-di(propan-2-yl)azanium;iodide Chemical compound [I-].C=1C=CC=CC=1C(C(N)=O)(CC[N+](C)(C(C)C)C(C)C)C1=CC=CC=C1 BFSMWENDZZIWPW-UHFFFAOYSA-N 0.000 description 1
- OMJKFYKNWZZKTK-UXBLZVDNSA-N (5E)-5-(dimethylaminohydrazinylidene)imidazole-4-carboxamide Chemical compound CN(C)N\N=C1\N=CN=C1C(N)=O OMJKFYKNWZZKTK-UXBLZVDNSA-N 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N (5S,5aR,8aR,9R)-5-[[(2R,4aR,6R,7R,8R,8aS)-7,8-dihydroxy-2-thiophen-2-yl-4,4a,6,7,8,8a-hexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy]-9-(4-hydroxy-3,5-dimethoxyphenyl)-5a,6,8a,9-tetrahydro-5H-[2]benzofuro[6,5-f][1,3]benzodioxol-8-one Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- DBPWSSGDRRHUNT-SJFWLOONSA-N (8R,9S,10R,13S,14S,17S)-17-acetyl-17-hydroxy-10,13-dimethyl-2,6,7,8,9,11,12,14,15,16-decahydro-1H-cyclopenta[a]phenanthren-3-one Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@](C(=O)C)(O)[C@@]1(C)CC2 DBPWSSGDRRHUNT-SJFWLOONSA-N 0.000 description 1
- YPVUHOBTCWJYNQ-SLHNCBLASA-N (8R,9S,13S,14S,17R)-17-ethenyl-17-hydroxy-13-methyl-1,2,4,6,7,8,9,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-3-one Chemical compound C1CC(=O)CC2=C1[C@H]1CC[C@](C)([C@](CC3)(O)C=C)[C@@H]3[C@@H]1CC2 YPVUHOBTCWJYNQ-SLHNCBLASA-N 0.000 description 1
- METKIMKYRPQLGS-GFCCVEGCSA-N (R)-atenolol Chemical compound CC(C)NC[C@@H](O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-GFCCVEGCSA-N 0.000 description 1
- KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical compound C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 description 1
- TWBNMYSKRDRHAT-RCWTXCDDSA-N (S)-timolol hemihydrate Chemical compound O.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1 TWBNMYSKRDRHAT-RCWTXCDDSA-N 0.000 description 1
- 229920000160 (ribonucleotides)n+m Polymers 0.000 description 1
- SNIOPGDIGTZGOP-UHFFFAOYSA-N 1,2,3-propanetrioltrinitrate Chemical compound [O-][N+](=O)OCC(O[N+]([O-])=O)CO[N+]([O-])=O SNIOPGDIGTZGOP-UHFFFAOYSA-N 0.000 description 1
- KEDVUOWPLAHMLZ-UHFFFAOYSA-N 1-cyano-3-[2-[(5-methyl-1H-imidazol-4-yl)methylsulfanyl]ethyl]-2-prop-2-ynylguanidine Chemical compound CC=1NC=NC=1CSCCNC(NC#N)=NCC#C KEDVUOWPLAHMLZ-UHFFFAOYSA-N 0.000 description 1
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 1
- NVUUMOOKVFONOM-GPBSYSOESA-N 19-Norprogesterone Chemical compound C1CC2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 NVUUMOOKVFONOM-GPBSYSOESA-N 0.000 description 1
- GJSURZIOUXUGAL-UHFFFAOYSA-N 2-((2,6-Dichlorophenyl)imino)imidazolidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 description 1
- PTUSXMWNCXRKAX-UHFFFAOYSA-N 2-(1H-inden-1-yl)acetic acid Chemical class C1=CC=C2C(CC(=O)O)C=CC2=C1 PTUSXMWNCXRKAX-UHFFFAOYSA-N 0.000 description 1
- RTGDFNSFWBGLEC-SYZQJQIISA-N 2-(morpholin-4-yl)ethyl (4E)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-2-benzofuran-5-yl)-4-methylhex-4-enoate Chemical compound COC1=C(C)C=2COC(=O)C=2C(O)=C1C\C=C(/C)CCC(=O)OCCN1CCOCC1 RTGDFNSFWBGLEC-SYZQJQIISA-N 0.000 description 1
- CTRPRMNBTVRDFH-UHFFFAOYSA-N 2-N-methyl-1,3,5-triazine-2,4,6-triamine Chemical class CNC1=NC(N)=NC(N)=N1 CTRPRMNBTVRDFH-UHFFFAOYSA-N 0.000 description 1
- TYCOFFBAZNSQOJ-UHFFFAOYSA-N 2-[4-(3-fluorophenyl)phenyl]propanoic acid Chemical compound C1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC(F)=C1 TYCOFFBAZNSQOJ-UHFFFAOYSA-N 0.000 description 1
- DEQJBORXLQWRGV-UHFFFAOYSA-N 2-hydroxypropanoic acid;iron Chemical compound [Fe].CC(O)C(O)=O.CC(O)C(O)=O DEQJBORXLQWRGV-UHFFFAOYSA-N 0.000 description 1
- PLIKAWJENQZMHA-UHFFFAOYSA-N 4-Aminophenol Chemical class NC1=CC=C(O)C=C1 PLIKAWJENQZMHA-UHFFFAOYSA-N 0.000 description 1
- RKWGIWYCVPQPMF-UHFFFAOYSA-N 4-chloro-N-[(propylamino)carbonyl]benzenesulfonamide Chemical compound CCCNC(=O)NS(=O)(=O)C1=CC=C(Cl)C=C1 RKWGIWYCVPQPMF-UHFFFAOYSA-N 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N 5-flurouricil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- BUCORZSTKDOEKQ-UHFFFAOYSA-N 7-chloro-4-hydroxy-N-methyl-5-phenyl-3H-1,4-benzodiazepin-2-imine Chemical compound C=12C=C(Cl)C=CC2=NC(=NC)CN(O)C=1C1=CC=CC=C1 BUCORZSTKDOEKQ-UHFFFAOYSA-N 0.000 description 1
- AOJJSUZBOXZQNB-TZSSRYMLSA-N ADRIAMYCIN 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 1
- 108060005293 AGA Proteins 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N AI2O3 Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 229940100198 ALKYLATING AGENTS Drugs 0.000 description 1
- 229940035676 ANALGESICS Drugs 0.000 description 1
- 229940033495 ANTIMALARIALS Drugs 0.000 description 1
- 229940100197 ANTIMETABOLITES Drugs 0.000 description 1
- 102100004323 ASPG Human genes 0.000 description 1
- 108010004463 Abciximab Proteins 0.000 description 1
- 229940022659 Acetaminophen Drugs 0.000 description 1
- BZKPWHYZMXOIDC-UHFFFAOYSA-N Acetazolamide Chemical compound CC(=O)NC1=NN=C(S(N)(=O)=O)S1 BZKPWHYZMXOIDC-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- 102000017910 Adrenergic receptor family Human genes 0.000 description 1
- 108060003345 Adrenergic receptor family Proteins 0.000 description 1
- 239000000275 Adrenocorticotropic Hormone Substances 0.000 description 1
- ARHWPKZXBHOEEE-UHFFFAOYSA-N Alclofenac Chemical compound OC(=O)CC1=CC=C(OCC=C)C(Cl)=C1 ARHWPKZXBHOEEE-UHFFFAOYSA-N 0.000 description 1
- OFCNXPDARWKPPY-UHFFFAOYSA-N Allopurinol Chemical compound OC1=NC=NC2=C1C=NN2 OFCNXPDARWKPPY-UHFFFAOYSA-N 0.000 description 1
- MANKSFVECICGLK-UHFFFAOYSA-K Aloxiprin Chemical compound [OH-].[Al+3].CC(=O)OC1=CC=CC=C1C([O-])=O.CC(=O)OC1=CC=CC=C1C([O-])=O MANKSFVECICGLK-UHFFFAOYSA-K 0.000 description 1
- PAZJSJFMUHDSTF-UHFFFAOYSA-N Alprenolol Chemical compound CC(C)NCC(O)COC1=CC=CC=C1CC=C PAZJSJFMUHDSTF-UHFFFAOYSA-N 0.000 description 1
- UUVWYPNAQBNQJQ-UHFFFAOYSA-N Altretamine Chemical compound CN(C)C1=NC(N(C)C)=NC(N(C)C)=N1 UUVWYPNAQBNQJQ-UHFFFAOYSA-N 0.000 description 1
- 229940024544 Aluminum aspirin Drugs 0.000 description 1
- SLXKOJJOQWFEFD-UHFFFAOYSA-N Aminocaproic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 description 1
- ROBVIMPUHSLWNV-UHFFFAOYSA-N Aminoglutethimide Chemical compound C=1C=C(N)C=CC=1C1(CC)CCC(=O)NC1=O ROBVIMPUHSLWNV-UHFFFAOYSA-N 0.000 description 1
- 229960003437 Aminoglutethimide Drugs 0.000 description 1
- HTIQEAQVCYTUBX-UHFFFAOYSA-N Amlodipine Chemical compound CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl HTIQEAQVCYTUBX-UHFFFAOYSA-N 0.000 description 1
- 229940008238 Amphetamine Sulfate Drugs 0.000 description 1
- 102000018984 Angiotensin Receptors Human genes 0.000 description 1
- 108010012129 Angiotensin Receptors Proteins 0.000 description 1
- XRCFXMGQEVUZFC-UHFFFAOYSA-N Anisindione Chemical compound C1=CC(OC)=CC=C1C1C(=O)C2=CC=CC=C2C1=O XRCFXMGQEVUZFC-UHFFFAOYSA-N 0.000 description 1
- RWZYAGGXGHYGMB-UHFFFAOYSA-N Anthranilic acid Chemical class NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 description 1
- 229940064005 Antibiotic throat preparations Drugs 0.000 description 1
- 229940083879 Antibiotics FOR TREATMENT OF HEMORRHOIDS AND ANAL FISSURES FOR TOPICAL USE Drugs 0.000 description 1
- 229940042052 Antibiotics for systemic use Drugs 0.000 description 1
- 229940019746 Antifibrinolytic amino acids Drugs 0.000 description 1
- 108020000948 Antisense Oligonucleotides Proteins 0.000 description 1
- 229940042786 Antitubercular Antibiotics Drugs 0.000 description 1
- 206010002855 Anxiety Diseases 0.000 description 1
- 206010057666 Anxiety disease Diseases 0.000 description 1
- 210000001742 Aqueous Humor Anatomy 0.000 description 1
- 229960002274 Atenolol Drugs 0.000 description 1
- 229960002028 Atropine Sulfate Drugs 0.000 description 1
- 229960005207 Auranofin Drugs 0.000 description 1
- XHVAWZZCDCWGBK-WYRLRVFGSA-M Aurothioglucose Chemical compound OC[C@H]1O[C@H](S[Au])[C@H](O)[C@@H](O)[C@@H]1O XHVAWZZCDCWGBK-WYRLRVFGSA-M 0.000 description 1
- 241000271566 Aves Species 0.000 description 1
- 229960002170 Azathioprine Drugs 0.000 description 1
- 239000005552 B01AC04 - Clopidogrel Substances 0.000 description 1
- 239000005528 B01AC05 - Ticlopidine Substances 0.000 description 1
- OYVAGSVQBOHSSS-WXFSZRTFSA-O Bleomycin Chemical class N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](OC1C(C(O)C(O)C(CO)O1)OC1C(C(OC(N)=O)C(O)C(CO)O1)O)C=1NC=NC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-WXFSZRTFSA-O 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- 210000001772 Blood Platelets Anatomy 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 235000003351 Brassica cretica Nutrition 0.000 description 1
- 240000008664 Brassica oleracea var. gongylodes Species 0.000 description 1
- 235000003343 Brassica rupestris Nutrition 0.000 description 1
- 241000219193 Brassicaceae Species 0.000 description 1
- JPKKQJKQTPNWTR-CHYDPLAESA-N CHEMBL3182372 Chemical compound O.OS(O)(=O)=O.O([C@H]1C[C@H]2CC[C@@H](C1)N2C)C(=O)C(CO)C1=CC=CC=C1.O([C@H]1C[C@H]2CC[C@@H](C1)N2C)C(=O)C(CO)C1=CC=CC=C1 JPKKQJKQTPNWTR-CHYDPLAESA-N 0.000 description 1
- WTGQALLALWYDJH-MOUKNHLCSA-N CHEMBL3185877 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
- 229960004015 Calcitonin Drugs 0.000 description 1
- 102400000113 Calcitonin Human genes 0.000 description 1
- 108060001064 Calcitonin Proteins 0.000 description 1
- 229960004494 Calcium Gluconate Drugs 0.000 description 1
- NEEHYRZPVYRGPP-IYEMJOQQSA-L Calcium gluconate Chemical compound [Ca+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O NEEHYRZPVYRGPP-IYEMJOQQSA-L 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- FAKRSMQSSFJEIM-RQJHMYQMSA-N Captopril Chemical compound SC[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O FAKRSMQSSFJEIM-RQJHMYQMSA-N 0.000 description 1
- OLESAACUTLOWQZ-UHFFFAOYSA-L Carboplatin Chemical compound O=C1O[Pt]([N]([H])([H])[H])([N]([H])([H])[H])OC(=O)C11CCC1 OLESAACUTLOWQZ-UHFFFAOYSA-L 0.000 description 1
- 229960004562 Carboplatin Drugs 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- OLVCFLKTBJRLHI-AXAPSJFSSA-N Cefamandole Chemical compound CN1N=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)[C@H](O)C=3C=CC=CC=3)[C@H]2SC1 OLVCFLKTBJRLHI-AXAPSJFSSA-N 0.000 description 1
- 210000003169 Central Nervous System Anatomy 0.000 description 1
- 229940106164 Cephalexin Drugs 0.000 description 1
- JWBOIMRXGHLCPP-UHFFFAOYSA-N Chloditan Chemical compound C=1C=CC=C(Cl)C=1C(C(Cl)Cl)C1=CC=C(Cl)C=C1 JWBOIMRXGHLCPP-UHFFFAOYSA-N 0.000 description 1
- 229960004630 Chlorambucil Drugs 0.000 description 1
- JCKYGMPEJWAADB-UHFFFAOYSA-N Chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 1
- 229960004782 Chlordiazepoxide Drugs 0.000 description 1
- 229960001616 Chlormadinone Acetate Drugs 0.000 description 1
- QMBJSIBWORFWQT-DFXBJWIESA-N Chlormadinone acetate Chemical compound C1=C(Cl)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 QMBJSIBWORFWQT-DFXBJWIESA-N 0.000 description 1
- HAWPXGHAZFHHAD-UHFFFAOYSA-N Chlormethine Chemical compound ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 1
- ZPEIMTDSQAKGNT-UHFFFAOYSA-N Chlorpromazine Chemical compound C1=C(Cl)C=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 ZPEIMTDSQAKGNT-UHFFFAOYSA-N 0.000 description 1
- 229960001076 Chlorpromazine Drugs 0.000 description 1
- 229960001761 Chlorpropamide Drugs 0.000 description 1
- 102000009660 Cholinergic Receptors Human genes 0.000 description 1
- 108010009685 Cholinergic Receptors Proteins 0.000 description 1
- 108010062540 Chorionic Gonadotropin Proteins 0.000 description 1
- 229940015047 Chorionic Gonadotropin Drugs 0.000 description 1
- 102000011022 Chorionic Gonadotropin Human genes 0.000 description 1
- 229960001380 Cimetidine Drugs 0.000 description 1
- CCGSUNCLSOWKJO-UHFFFAOYSA-N Cimetidine Chemical compound N#CNC(=N/C)\NCCSCC1=NC=N[C]1C CCGSUNCLSOWKJO-UHFFFAOYSA-N 0.000 description 1
- 229960003009 Clopidogrel Drugs 0.000 description 1
- GKTWGGQPFAXNFI-HNNXBMFYSA-N Clopidogrel Chemical compound C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl GKTWGGQPFAXNFI-HNNXBMFYSA-N 0.000 description 1
- 210000004087 Cornea Anatomy 0.000 description 1
- 229940064701 Corticosteroid nasal preparations for topical use Drugs 0.000 description 1
- 229960001334 Corticosteroids Drugs 0.000 description 1
- 101800000414 Corticotropin Proteins 0.000 description 1
- MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 description 1
- ITRJWOMZKQRYTA-RFZYENFJSA-N Cortisone acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)CC2=O ITRJWOMZKQRYTA-RFZYENFJSA-N 0.000 description 1
- 241000938605 Crocodylia Species 0.000 description 1
- 229960004397 Cyclophosphamide Drugs 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- 229940119017 Cyclosporine Drugs 0.000 description 1
- 108010036949 Cyclosporine Proteins 0.000 description 1
- 229960000684 Cytarabine Drugs 0.000 description 1
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytosar Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 1
- STQGQHZAVUOBTE-VGBVRHCVSA-N DAUNOMYCIN 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(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 1
- 229940030606 DIURETICS Drugs 0.000 description 1
- 108010092160 Dactinomycin Proteins 0.000 description 1
- 229960000640 Dactinomycin Drugs 0.000 description 1
- 229960000975 Daunorubicin Drugs 0.000 description 1
- 206010051055 Deep vein thrombosis Diseases 0.000 description 1
- AAOVKJBEBIDNHE-UHFFFAOYSA-N Diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 1
- JZUFKLXOESDKRF-UHFFFAOYSA-N Dichlothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 description 1
- LTMHDMANZUZIPE-PUGKRICDSA-N Digoxin Chemical compound C1[C@H](O)[C@H](O)[C@@H](C)O[C@H]1O[C@@H]1[C@@H](C)O[C@@H](O[C@@H]2[C@H](O[C@@H](O[C@@H]3C[C@@H]4[C@]([C@@H]5[C@H]([C@]6(CC[C@@H]([C@@]6(C)[C@H](O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)C[C@@H]2O)C)C[C@@H]1O LTMHDMANZUZIPE-PUGKRICDSA-N 0.000 description 1
- LTMHDMANZUZIPE-AMTYYWEZSA-N Digoxin Natural products O([C@H]1[C@H](C)O[C@H](O[C@@H]2C[C@@H]3[C@@](C)([C@@H]4[C@H]([C@]5(O)[C@](C)([C@H](O)C4)[C@H](C4=CC(=O)OC4)CC5)CC3)CC2)C[C@@H]1O)[C@H]1O[C@H](C)[C@@H](O[C@H]2O[C@@H](C)[C@H](O)[C@@H](O)C2)[C@@H](O)C1 LTMHDMANZUZIPE-AMTYYWEZSA-N 0.000 description 1
- HSUGRBWQSSZJOP-RTWAWAEBSA-N Diltiazem Chemical compound C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CCN(C)C)C2=CC=CC=C2S1 HSUGRBWQSSZJOP-RTWAWAEBSA-N 0.000 description 1
- JYGLAHSAISAEAL-UHFFFAOYSA-N Diphenadione Chemical compound O=C1C2=CC=CC=C2C(=O)C1C(=O)C(C=1C=CC=CC=1)C1=CC=CC=C1 JYGLAHSAISAEAL-UHFFFAOYSA-N 0.000 description 1
- OGAKLTJNUQRZJU-UHFFFAOYSA-N Diphenidol Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(O)CCCN1CCCCC1 OGAKLTJNUQRZJU-UHFFFAOYSA-N 0.000 description 1
- 229960002768 Dipyridamole Drugs 0.000 description 1
- IZEKFCXSFNUWAM-UHFFFAOYSA-N Dipyridamole Chemical compound C=12N=C(N(CCO)CCO)N=C(N3CCCCC3)C2=NC(N(CCO)CCO)=NC=1N1CCCCC1 IZEKFCXSFNUWAM-UHFFFAOYSA-N 0.000 description 1
- 229960004679 Doxorubicin Drugs 0.000 description 1
- 210000000613 Ear Canal Anatomy 0.000 description 1
- 208000005189 Embolism Diseases 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 229960000873 Enalapril Drugs 0.000 description 1
- 108010061435 Enalapril Proteins 0.000 description 1
- GBXSMTUPTTWBMN-XIRDDKMYSA-N Enalapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(O)=O)CC1=CC=CC=C1 GBXSMTUPTTWBMN-XIRDDKMYSA-N 0.000 description 1
- 108010066671 Enalaprilat Proteins 0.000 description 1
- LZFZMUMEGBBDTC-QEJZJMRPSA-N Enalaprilat Chemical compound C([C@H](N[C@@H](C)C(=O)N1[C@@H](CCC1)C(O)=O)C(O)=O)CC1=CC=CC=C1 LZFZMUMEGBBDTC-QEJZJMRPSA-N 0.000 description 1
- 206010014801 Endophthalmitis Diseases 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 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 1
- 102000003951 Erythropoietin Human genes 0.000 description 1
- 108090000394 Erythropoietin Proteins 0.000 description 1
- 229960005309 Estradiol Drugs 0.000 description 1
- 229950007285 Etintidine Drugs 0.000 description 1
- BFPYWIDHMRZLRN-SLHNCBLASA-N Etivex Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 BFPYWIDHMRZLRN-SLHNCBLASA-N 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N Etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 229960005420 Etoposide Drugs 0.000 description 1
- 208000009745 Eye Disease Diseases 0.000 description 1
- 229960001596 Famotidine Drugs 0.000 description 1
- XUFQPHANEAPEMJ-UHFFFAOYSA-N Famotidine Chemical compound NC(N)=NC1=NC(CSCCC(N)=NS(N)(=O)=O)=CS1 XUFQPHANEAPEMJ-UHFFFAOYSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 210000001105 Femoral Artery Anatomy 0.000 description 1
- ZPAKPRAICRBAOD-UHFFFAOYSA-N Fenbufen Chemical compound C1=CC(C(=O)CCC(=O)O)=CC=C1C1=CC=CC=C1 ZPAKPRAICRBAOD-UHFFFAOYSA-N 0.000 description 1
- 229960001419 Fenoprofen Drugs 0.000 description 1
- RDJGLLICXDHJDY-UHFFFAOYSA-N Fenoprofen Chemical compound OC(=O)C(C)C1=CC=CC(OC=2C=CC=CC=2)=C1 RDJGLLICXDHJDY-UHFFFAOYSA-N 0.000 description 1
- 210000003811 Fingers Anatomy 0.000 description 1
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N Floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 1
- 229960000961 Floxuridine Drugs 0.000 description 1
- 229960002949 Fluorouracil Drugs 0.000 description 1
- 229950001284 Fluprofen Drugs 0.000 description 1
- SYTBZMRGLBWNTM-UHFFFAOYSA-N Flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 description 1
- 108010079345 Follicle Stimulating Hormone Proteins 0.000 description 1
- 229940028334 Follicle Stimulating Hormone Drugs 0.000 description 1
- 102000012673 Follicle Stimulating Hormone Human genes 0.000 description 1
- 102100000899 GNRH1 Human genes 0.000 description 1
- 229960000457 Gallopamil Drugs 0.000 description 1
- XQLWNAFCTODIRK-UHFFFAOYSA-N Gallopamil Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC(OC)=C(OC)C(OC)=C1 XQLWNAFCTODIRK-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229960004666 Glucagon Drugs 0.000 description 1
- 108060003199 Glucagon Proteins 0.000 description 1
- MASNOZXLGMXCHN-ZLPAWPGGSA-N Glucagonum Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 239000000579 Gonadotropin-Releasing Hormone Substances 0.000 description 1
- 108010051696 Growth Hormone Proteins 0.000 description 1
- 102000018997 Growth Hormone Human genes 0.000 description 1
- 229940093922 Gynecological Antibiotics Drugs 0.000 description 1
- 229940005535 HYPNOTICS AND SEDATIVES Drugs 0.000 description 1
- LNEPOXFFQSENCJ-UHFFFAOYSA-N Haloperidol Chemical compound C1CC(O)(C=2C=CC(Cl)=CC=2)CCN1CCCC(=O)C1=CC=C(F)C=C1 LNEPOXFFQSENCJ-UHFFFAOYSA-N 0.000 description 1
- 229960002897 Heparin Drugs 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 229960003444 IMMUNOSUPPRESSANTS Drugs 0.000 description 1
- 102100019438 ITGAV Human genes 0.000 description 1
- 229960000908 Idarubicin Drugs 0.000 description 1
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin hydrochloride 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
- 210000003090 Iliac Artery Anatomy 0.000 description 1
- RJMIEHBSYVWVIN-UHFFFAOYSA-N Indoprofen Chemical compound C1=CC(C(C(O)=O)C)=CC=C1N1C(=O)C2=CC=CC=C2C1 RJMIEHBSYVWVIN-UHFFFAOYSA-N 0.000 description 1
- 229940060367 Inert Ingredients Drugs 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N Intaxel 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
- 229940047124 Interferons Drugs 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 229940047122 Interleukins Drugs 0.000 description 1
- 102000015696 Interleukins Human genes 0.000 description 1
- 108010063738 Interleukins Proteins 0.000 description 1
- BAUYGSIQEAFULO-UHFFFAOYSA-L Iron(II) sulfate Chemical compound [Fe+2].[O-]S([O-])(=O)=O BAUYGSIQEAFULO-UHFFFAOYSA-L 0.000 description 1
- 229960001543 Isopropamide Iodide Drugs 0.000 description 1
- 229960000201 Isosorbide Dinitrate Drugs 0.000 description 1
- MOYKHGMNXAOIAT-JGWLITMVSA-N Isosorbide dinitrate Chemical compound [O-][N+](=O)O[C@H]1CO[C@@H]2[C@H](O[N+](=O)[O-])CO[C@@H]21 MOYKHGMNXAOIAT-JGWLITMVSA-N 0.000 description 1
- 229940090046 Jet Injector Drugs 0.000 description 1
- DKYWVDODHFEZIM-UHFFFAOYSA-N Ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 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
- DCXYFEDJOCDNAF-UWTATZPHSA-N L-Asparagine Natural products OC(=O)[C@H](N)CC(N)=O DCXYFEDJOCDNAF-UWTATZPHSA-N 0.000 description 1
- 208000002473 Lacerations Diseases 0.000 description 1
- 241001236653 Lavinia exilicauda Species 0.000 description 1
- ZBIAKUMOEKILTF-UHFFFAOYSA-N Lidoflazine Chemical compound CC1=CC=CC(C)=C1NC(=O)CN1CCN(CCCC(C=2C=CC(F)=CC=2)C=2C=CC(F)=CC=2)CC1 ZBIAKUMOEKILTF-UHFFFAOYSA-N 0.000 description 1
- 229960001941 Lidoflazine Drugs 0.000 description 1
- 102000004895 Lipoproteins Human genes 0.000 description 1
- 108090001030 Lipoproteins Proteins 0.000 description 1
- 229960002394 Lisinopril Drugs 0.000 description 1
- 108010007859 Lisinopril Proteins 0.000 description 1
- 229960005015 Local anesthetics Drugs 0.000 description 1
- 229940083877 Local anesthetics for treatment of hemorrhoids and anal fissures for topical use Drugs 0.000 description 1
- ZFMITUMMTDLWHR-UHFFFAOYSA-N Loniten Chemical compound NC1=[N+]([O-])C(N)=CC(N2CCCCC2)=N1 ZFMITUMMTDLWHR-UHFFFAOYSA-N 0.000 description 1
- 229940040129 Luteinizing Hormone Drugs 0.000 description 1
- 102000009151 Luteinizing Hormone Human genes 0.000 description 1
- 108010073521 Luteinizing Hormone Proteins 0.000 description 1
- 229940035363 MUSCLE RELAXANTS Drugs 0.000 description 1
- 208000001344 Macular Edema Diseases 0.000 description 1
- 206010025415 Macular oedema Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229960004961 Mechlorethamine Drugs 0.000 description 1
- OCJYIGYOJCODJL-UHFFFAOYSA-N Meclizine Chemical compound CC1=CC=CC(CN2CCN(CC2)C(C=2C=CC=CC=2)C=2C=CC(Cl)=CC=2)=C1 OCJYIGYOJCODJL-UHFFFAOYSA-N 0.000 description 1
- 229940018415 Meclizine Hydrochloride Drugs 0.000 description 1
- SBDNJUWAMKYJOX-UHFFFAOYSA-N Meclofenamic Acid Chemical compound CC1=CC=C(Cl)C(NC=2C(=CC=CC=2)C(O)=O)=C1Cl SBDNJUWAMKYJOX-UHFFFAOYSA-N 0.000 description 1
- HYYBABOKPJLUIN-UHFFFAOYSA-N Mefenamic acid Chemical compound CC1=CC=CC(NC=2C(=CC=CC=2)C(O)=O)=C1C HYYBABOKPJLUIN-UHFFFAOYSA-N 0.000 description 1
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N Melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 1
- IMSSROKUHAOUJS-MJCUULBUSA-N Mestranol Chemical compound C1C[C@]2(C)[C@@](C#C)(O)CC[C@H]2[C@@H]2CCC3=CC(OC)=CC=C3[C@H]21 IMSSROKUHAOUJS-MJCUULBUSA-N 0.000 description 1
- 229960002931 Methacholine Chloride Drugs 0.000 description 1
- 229960002532 Methamphetamine Hydrochloride Drugs 0.000 description 1
- FLOSMHQXBMRNHR-DAXSKMNVSA-N Methazolamide Chemical compound CC(=O)\N=C1/SC(S(N)(=O)=O)=NN1C FLOSMHQXBMRNHR-DAXSKMNVSA-N 0.000 description 1
- 229960004083 Methazolamide Drugs 0.000 description 1
- CJCSPKMFHVPWAR-JTQLQIEISA-N Methyldopa Chemical compound OC(=O)[C@](N)(C)CC1=CC=C(O)C(O)=C1 CJCSPKMFHVPWAR-JTQLQIEISA-N 0.000 description 1
- 229960000615 Methyldopa Drugs 0.000 description 1
- 229960001033 Methylphenidate Hydrochloride Drugs 0.000 description 1
- GCKMFJBGXUYNAG-HLXURNFRSA-N Methyltestosterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@](C)(O)[C@@]1(C)CC2 GCKMFJBGXUYNAG-HLXURNFRSA-N 0.000 description 1
- PZRHRDRVRGEVNW-UHFFFAOYSA-N Milrinone Chemical compound N1C(=O)C(C#N)=CC(C=2C=CN=CC=2)=C1C PZRHRDRVRGEVNW-UHFFFAOYSA-N 0.000 description 1
- 229960003632 Minoxidil Drugs 0.000 description 1
- 229960004857 Mitomycin Drugs 0.000 description 1
- 229960000350 Mitotane Drugs 0.000 description 1
- KKZJGLLVHKMTCM-UHFFFAOYSA-N Mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 1
- 229960001156 Mitoxantrone Drugs 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 229940083876 Muscle relaxants FOR TREATMENT OF HEMORRHOIDS AND ANAL FISSURES FOR TOPICAL USE Drugs 0.000 description 1
- 210000002027 Muscle, Skeletal Anatomy 0.000 description 1
- 210000002460 Muscle, Smooth Anatomy 0.000 description 1
- 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 1
- JFNWFXVFBDDWCX-UHFFFAOYSA-N N-(4-aminophenyl)sulfonyl-N-(3,4-dimethyl-1,2-oxazol-5-yl)acetamide Chemical compound C=1C=C(N)C=CC=1S(=O)(=O)N(C(=O)C)C=1ON=C(C)C=1C JFNWFXVFBDDWCX-UHFFFAOYSA-N 0.000 description 1
- XLXSAKCOAKORKW-KPKRHBJMSA-N N-[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[2-[[(2S)-1-[[(2S)-1-[(2S)-2-[(2-amino-2-oxoethyl)carbamoyl]pyrrolidin-1-yl]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-2-oxoethyl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl] Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)C1NC(=O)CC1)C1=CC=C(O)C=C1 XLXSAKCOAKORKW-KPKRHBJMSA-N 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
- 206010029113 Neovascularisation Diseases 0.000 description 1
- 229960001783 Nicardipine Drugs 0.000 description 1
- ZBBHBTPTTSWHBA-UHFFFAOYSA-N Nicardipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN(C)CC=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 ZBBHBTPTTSWHBA-UHFFFAOYSA-N 0.000 description 1
- 229960000715 Nimodipine Drugs 0.000 description 1
- UIAGMCDKSXEBJQ-UHFFFAOYSA-N Nimodipine Chemical compound COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1C1=CC=CC([N+]([O-])=O)=C1 UIAGMCDKSXEBJQ-UHFFFAOYSA-N 0.000 description 1
- 229960000227 Nisoldipine Drugs 0.000 description 1
- 229960005425 Nitrendipine Drugs 0.000 description 1
- PVHUJELLJLJGLN-UHFFFAOYSA-N Nitrendipine Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC([N+]([O-])=O)=C1 PVHUJELLJLJGLN-UHFFFAOYSA-N 0.000 description 1
- 239000000006 Nitroglycerin Substances 0.000 description 1
- 229940014995 Nitroglycerin Drugs 0.000 description 1
- SGXXNSQHWDMGGP-IZZDOVSWSA-N Nizatidine Chemical compound [O-][N+](=O)\C=C(/NC)NCCSCC1=CSC(CN(C)C)=N1 SGXXNSQHWDMGGP-IZZDOVSWSA-N 0.000 description 1
- 229960004872 Nizatidine Drugs 0.000 description 1
- 229940053934 Norethindrone Drugs 0.000 description 1
- 229960001858 Norethynodrel Drugs 0.000 description 1
- ICTXHFFSOAJUMG-SLHNCBLASA-N Norethynodrel Chemical compound C1CC(=O)CC2=C1[C@H]1CC[C@](C)([C@](CC3)(O)C#C)[C@@H]3[C@@H]1CC2 ICTXHFFSOAJUMG-SLHNCBLASA-N 0.000 description 1
- 229940053938 Norgestrel Drugs 0.000 description 1
- 102000011931 Nucleoproteins Human genes 0.000 description 1
- 108010061100 Nucleoproteins Proteins 0.000 description 1
- 101710008205 OXT Proteins 0.000 description 1
- 102100017240 OXT Human genes 0.000 description 1
- 210000000956 Olfactory Bulb Anatomy 0.000 description 1
- 229920000272 Oligonucleotide Polymers 0.000 description 1
- 241000283898 Ovis Species 0.000 description 1
- 229960001723 Oxytocin Drugs 0.000 description 1
- XNOPRXBHLZRZKH-DSZYJQQASA-N Oxytocin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@H](N)C(=O)N1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)NCC(N)=O)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 XNOPRXBHLZRZKH-DSZYJQQASA-N 0.000 description 1
- 229960001592 Paclitaxel Drugs 0.000 description 1
- 210000003254 Palate Anatomy 0.000 description 1
- 229960002340 Pentostatin Drugs 0.000 description 1
- FPVKHBSQESCIEP-JQCXWYLXSA-N Pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 description 1
- 210000000578 Peripheral Nerves Anatomy 0.000 description 1
- 206010034636 Peripheral vascular disease Diseases 0.000 description 1
- HTYIXCKSEQQCJO-UHFFFAOYSA-N Phenaglycodol Chemical compound CC(C)(O)C(C)(O)C1=CC=C(Cl)C=C1 HTYIXCKSEQQCJO-UHFFFAOYSA-N 0.000 description 1
- 229950005116 Phenaglycodol Drugs 0.000 description 1
- ICFJFFQQTFMIBG-UHFFFAOYSA-N Phenformin Chemical compound NC(=N)NC(=N)NCCC1=CC=CC=C1 ICFJFFQQTFMIBG-UHFFFAOYSA-N 0.000 description 1
- 229960002315 Phenmetrazine Hydrochloride Drugs 0.000 description 1
- VJNXVAVKCZJOFQ-UHFFFAOYSA-N Phenmetrazine hydrochloride Chemical compound Cl.CC1NCCOC1C1=CC=CC=C1 VJNXVAVKCZJOFQ-UHFFFAOYSA-N 0.000 description 1
- 229960002895 Phenylbutazone Drugs 0.000 description 1
- 229960002139 Pilocarpine Hydrochloride Drugs 0.000 description 1
- QCHFTSOMWOSFHM-WPRPVWTQSA-N Pilopine HS Chemical compound C1OC(=O)[C@@H](CC)[C@H]1CC1=CN=CN1C QCHFTSOMWOSFHM-WPRPVWTQSA-N 0.000 description 1
- QYSPLQLAKJAUJT-UHFFFAOYSA-N Piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 description 1
- 102000006877 Pituitary Hormones Human genes 0.000 description 1
- 108010047386 Pituitary Hormones Proteins 0.000 description 1
- 108010038512 Platelet-Derived Growth Factor Proteins 0.000 description 1
- 102000010780 Platelet-Derived Growth Factor Human genes 0.000 description 1
- 239000004696 Poly ether ether ketone Substances 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N Prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- WWYNJERNGUHSAO-XUDSTZEESA-N Previfem Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](CC)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 WWYNJERNGUHSAO-XUDSTZEESA-N 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 229960003253 Procainamide Hydrochloride Drugs 0.000 description 1
- CPTBDICYNRMXFX-UHFFFAOYSA-N Procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 1
- RJKFOVLPORLFTN-STHVQZNPSA-N Progesterone Natural products O=C(C)[C@@H]1[C@@]2(C)[C@H]([C@H]3[C@@H]([C@]4(C)C(=CC(=O)CC4)CC3)CC2)CC1 RJKFOVLPORLFTN-STHVQZNPSA-N 0.000 description 1
- AQHHHDLHHXJYJD-UHFFFAOYSA-N Proprasylyt Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 description 1
- 229940082622 Prostaglandin cardiac therapy preparations Drugs 0.000 description 1
- 229940077717 Prostaglandin drugs for peptic ulcer and gastro-oesophageal reflux disease (GORD) Drugs 0.000 description 1
- 102100000775 REN Human genes 0.000 description 1
- 229960003401 Ramipril Drugs 0.000 description 1
- HDACQVRGBOVJII-JBDAPHQKSA-N Ramipril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](C[C@@H]2CCC[C@@H]21)C(O)=O)CC1=CC=CC=C1 HDACQVRGBOVJII-JBDAPHQKSA-N 0.000 description 1
- 229960000620 Ranitidine Drugs 0.000 description 1
- VMXUWOKSQNHOCA-LCYFTJDESA-N Ranitidine Chemical compound [O-][N+](=O)/C=C(/NC)NCCSCC1=CC=C(CN(C)C)O1 VMXUWOKSQNHOCA-LCYFTJDESA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 108090000783 Renin Proteins 0.000 description 1
- 229960002917 Reteplase Drugs 0.000 description 1
- 206010038848 Retinal detachment Diseases 0.000 description 1
- 229940058287 Salicylic acid derivative anticestodals Drugs 0.000 description 1
- 229960000553 Somatostatin Drugs 0.000 description 1
- 102000005157 Somatostatin Human genes 0.000 description 1
- 108010056088 Somatostatin Proteins 0.000 description 1
- 210000002784 Stomach Anatomy 0.000 description 1
- 229960001052 Streptozocin Drugs 0.000 description 1
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N Streptozotocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 1
- MNQYNQBOVCBZIQ-JQOFMKNESA-A Sucralfate Chemical compound O[Al](O)OS(=O)(=O)O[C@@H]1[C@@H](OS(=O)(=O)O[Al](O)O)[C@H](OS(=O)(=O)O[Al](O)O)[C@@H](COS(=O)(=O)O[Al](O)O)O[C@H]1O[C@@]1(COS(=O)(=O)O[Al](O)O)[C@@H](OS(=O)(=O)O[Al](O)O)[C@H](OS(=O)(=O)O[Al](O)O)[C@@H](OS(=O)(=O)O[Al](O)O)O1 MNQYNQBOVCBZIQ-JQOFMKNESA-A 0.000 description 1
- 229960004291 Sucralfate Drugs 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 239000000150 Sympathomimetic Substances 0.000 description 1
- 229940064707 Sympathomimetics Drugs 0.000 description 1
- RJKFOVLPORLFTN-LEKSSAKUSA-N Syngestrets Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 1
- 229960001278 Teniposide Drugs 0.000 description 1
- 229960004869 Thiethylperazine Drugs 0.000 description 1
- XCTYLCDETUVOIP-UHFFFAOYSA-N Thiethylperazine Chemical compound C12=CC(SCC)=CC=C2SC2=CC=CC=C2N1CCCN1CCN(C)CC1 XCTYLCDETUVOIP-UHFFFAOYSA-N 0.000 description 1
- FOCVUCIESVLUNU-UHFFFAOYSA-N ThioTEPA Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 1
- 229960005454 Thioguanine Drugs 0.000 description 1
- 229960001196 Thiotepa Drugs 0.000 description 1
- 210000003813 Thumb Anatomy 0.000 description 1
- 102000011923 Thyrotropin Human genes 0.000 description 1
- 108010061174 Thyrotropin Proteins 0.000 description 1
- 229960005001 Ticlopidine Drugs 0.000 description 1
- PHWBOXQYWZNQIN-UHFFFAOYSA-N Ticlopidine Chemical compound ClC1=CC=CC=C1CN1CC(C=CS2)=C2CC1 PHWBOXQYWZNQIN-UHFFFAOYSA-N 0.000 description 1
- 108090000373 Tissue plasminogen activator Proteins 0.000 description 1
- 102000003978 Tissue plasminogen activator Human genes 0.000 description 1
- 229960002277 Tolazamide Drugs 0.000 description 1
- OUDSBRTVNLOZBN-UHFFFAOYSA-N Tolazamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)NN1CCCCCC1 OUDSBRTVNLOZBN-UHFFFAOYSA-N 0.000 description 1
- 229940024982 Topical Antifungal Antibiotics Drugs 0.000 description 1
- 239000004963 Torlon Substances 0.000 description 1
- 229920003997 Torlon® Polymers 0.000 description 1
- 229920004738 ULTEM® Polymers 0.000 description 1
- 229960005356 Urokinase Drugs 0.000 description 1
- 108090000435 Urokinase-type plasminogen activator Proteins 0.000 description 1
- 102000003990 Urokinase-type plasminogen activator Human genes 0.000 description 1
- 206010046851 Uveitis Diseases 0.000 description 1
- 229940029983 VITAMINS Drugs 0.000 description 1
- 210000003462 Veins Anatomy 0.000 description 1
- 229960003048 Vinblastine Drugs 0.000 description 1
- HOFQVRTUGATRFI-XQKSVPLYSA-N Vinblastine 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=C1N=C1[C]2C=CC=C1 HOFQVRTUGATRFI-XQKSVPLYSA-N 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
- 241000863480 Vinca Species 0.000 description 1
- 229960002726 Vincamine Drugs 0.000 description 1
- 229960004528 Vincristine Drugs 0.000 description 1
- 229940021016 Vitamin IV solution additives Drugs 0.000 description 1
- 210000004127 Vitreous Body Anatomy 0.000 description 1
- 108010048673 Vitronectin Receptors Proteins 0.000 description 1
- ZXVNMYWKKDOREA-UHFFFAOYSA-N Zomepirac Chemical compound C1=C(CC(O)=O)N(C)C(C(=O)C=2C=CC(Cl)=CC=2)=C1C ZXVNMYWKKDOREA-UHFFFAOYSA-N 0.000 description 1
- 229960000446 abciximab Drugs 0.000 description 1
- 229960000571 acetazolamide Drugs 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 1
- 230000001780 adrenocortical Effects 0.000 description 1
- 239000003732 agents acting on the eye Substances 0.000 description 1
- 239000003741 agents affecting lipid metabolism Substances 0.000 description 1
- 229960005142 alclofenac Drugs 0.000 description 1
- 239000003619 algicide Substances 0.000 description 1
- 229930013930 alkaloids Natural products 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229960003459 allopurinol Drugs 0.000 description 1
- 229960002213 alprenolol Drugs 0.000 description 1
- 229960000473 altretamine Drugs 0.000 description 1
- 229960002734 amfetamine Drugs 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229960002684 aminocaproic acid Drugs 0.000 description 1
- 229960000528 amlodipine Drugs 0.000 description 1
- 230000000202 analgesic Effects 0.000 description 1
- 239000004037 angiogenesis inhibitor Substances 0.000 description 1
- 230000002491 angiogenic Effects 0.000 description 1
- 229960002138 anisindione Drugs 0.000 description 1
- 230000003042 antagnostic Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000001396 anti-anti-diuretic Effects 0.000 description 1
- 230000002429 anti-coagulation Effects 0.000 description 1
- 230000001773 anti-convulsant Effects 0.000 description 1
- 230000000118 anti-eoplastic Effects 0.000 description 1
- 230000000078 anti-malarial Effects 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 230000002095 anti-migrative Effects 0.000 description 1
- 230000000111 anti-oxidant Effects 0.000 description 1
- 239000000051 antiandrogen Substances 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 239000003430 antimalarial agent Substances 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 229940045686 antimetabolites antineoplastic Purine analogs Drugs 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000003080 antimitotic agent Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940045713 antineoplastic alkylating drugs Ethylene imines Drugs 0.000 description 1
- 229940045688 antineoplastic antimetabolites Pyrimidine analogues Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000003096 antiparasitic agent Substances 0.000 description 1
- 239000000939 antiparkinson agent Substances 0.000 description 1
- 239000000074 antisense oligonucleotide Substances 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- KBZOIRJILGZLEJ-LGYYRGKSSA-N argipressin Chemical compound C([C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@@H](C(N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N1)=O)N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)NCC(N)=O)C1=CC=CC=C1 KBZOIRJILGZLEJ-LGYYRGKSSA-N 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- AUJRCFUBUPVWSZ-XTZHGVARSA-M auranofin Chemical compound CCP(CC)(CC)=[Au]S[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O AUJRCFUBUPVWSZ-XTZHGVARSA-M 0.000 description 1
- 229960001799 aurothioglucose Drugs 0.000 description 1
- LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 description 1
- HDWIHXWEUNVBIY-UHFFFAOYSA-N bendroflumethiazidum Chemical compound C1=C(C(F)(F)F)C(S(=O)(=O)N)=CC(S(N2)(=O)=O)=C1NC2CC1=CC=CC=C1 HDWIHXWEUNVBIY-UHFFFAOYSA-N 0.000 description 1
- ANFSNXAXVLRZCG-RSAXXLAASA-N benzphetamine hydrochloride Chemical compound [Cl-].C([C@H](C)[NH+](C)CC=1C=CC=CC=1)C1=CC=CC=C1 ANFSNXAXVLRZCG-RSAXXLAASA-N 0.000 description 1
- 239000003139 biocide Substances 0.000 description 1
- 201000004569 blindness Diseases 0.000 description 1
- BBBFJLBPOGFECG-VJVYQDLKSA-N calcitonin Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(N)=O)C(C)C)C(=O)[C@@H]1CSSC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 BBBFJLBPOGFECG-VJVYQDLKSA-N 0.000 description 1
- 239000004227 calcium gluconate Substances 0.000 description 1
- 235000013927 calcium gluconate Nutrition 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229960000830 captopril Drugs 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 229960005243 carmustine Drugs 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 230000003822 cell turnover Effects 0.000 description 1
- 229940083181 centrally acting adntiadrenergic agents Methyldopa Drugs 0.000 description 1
- 229940084959 cephalexin hydrochloride Drugs 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 230000001684 chronic Effects 0.000 description 1
- 229960001265 ciclosporin Drugs 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 229960002436 cladribine Drugs 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- 229960002896 clonidine Drugs 0.000 description 1
- 229960001338 colchicine Drugs 0.000 description 1
- 238000010961 commercial manufacture process Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000003433 contraceptive agent Substances 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960000258 corticotropin Drugs 0.000 description 1
- IDLFZVILOHSSID-OVLDLUHVSA-N corticotropin Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)NC(=O)[C@@H](N)CO)C1=CC=C(O)C=C1 IDLFZVILOHSSID-OVLDLUHVSA-N 0.000 description 1
- 229960004544 cortisone Drugs 0.000 description 1
- 229960003290 cortisone acetate Drugs 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 229920003013 deoxyribonucleic acid Polymers 0.000 description 1
- 239000000645 desinfectant Substances 0.000 description 1
- 230000000249 desinfective Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229960003529 diazepam Drugs 0.000 description 1
- 229960001259 diclofenac Drugs 0.000 description 1
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 1
- 229960005156 digoxin Drugs 0.000 description 1
- 229960004166 diltiazem Drugs 0.000 description 1
- 229960000267 diphenadione Drugs 0.000 description 1
- 229960003520 diphenidol Drugs 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 229960002680 enalaprilat Drugs 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 229920003247 engineering thermoplastic Polymers 0.000 description 1
- 229960003276 erythromycin Drugs 0.000 description 1
- 229940105423 erythropoietin Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 229960002568 ethinylestradiol Drugs 0.000 description 1
- 230000004424 eye movement Effects 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 229960001395 fenbufen Drugs 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 229940037907 ferrous lactate Drugs 0.000 description 1
- 239000004225 ferrous lactate Substances 0.000 description 1
- 235000013925 ferrous lactate Nutrition 0.000 description 1
- 229960001781 ferrous sulfate Drugs 0.000 description 1
- 239000011790 ferrous sulphate Substances 0.000 description 1
- 235000003891 ferrous sulphate Nutrition 0.000 description 1
- 239000003527 fibrinolytic agent Substances 0.000 description 1
- 229960002390 flurbiprofen Drugs 0.000 description 1
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical class C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 230000000855 fungicidal Effects 0.000 description 1
- 239000000417 fungicide Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000002070 germicidal Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 150000004676 glycans Polymers 0.000 description 1
- 229960003711 glyceryl trinitrate Drugs 0.000 description 1
- 150000002344 gold compounds Chemical class 0.000 description 1
- 239000007952 growth promoter Substances 0.000 description 1
- 229960003878 haloperidol Drugs 0.000 description 1
- 201000010238 heart disease Diseases 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 230000002363 herbicidal Effects 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 229960002003 hydrochlorothiazide Drugs 0.000 description 1
- 229960001330 hydroxycarbamide Drugs 0.000 description 1
- VSNHCAURESNICA-UHFFFAOYSA-N hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 1
- 229940027318 hydroxyurea Drugs 0.000 description 1
- 239000005554 hypnotics and sedatives Substances 0.000 description 1
- 230000002218 hypoglycaemic Effects 0.000 description 1
- 239000000960 hypophysis hormone Substances 0.000 description 1
- 238000002649 immunization Methods 0.000 description 1
- 230000003053 immunization Effects 0.000 description 1
- 230000001861 immunosuppresant Effects 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 229960004187 indoprofen Drugs 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000000977 initiatory Effects 0.000 description 1
- 150000002484 inorganic compounds Chemical class 0.000 description 1
- 230000000749 insecticidal Effects 0.000 description 1
- 239000002917 insecticide Substances 0.000 description 1
- 229940079866 intestinal antibiotics Drugs 0.000 description 1
- 238000009114 investigational therapy Methods 0.000 description 1
- 229910000359 iron(II) sulfate Inorganic materials 0.000 description 1
- 229960000991 ketoprofen Drugs 0.000 description 1
- 229960004752 ketorolac Drugs 0.000 description 1
- 150000002605 large molecules Chemical class 0.000 description 1
- 229960004400 levonorgestrel Drugs 0.000 description 1
- 230000000670 limiting Effects 0.000 description 1
- RLAWWYSOJDYHDC-BZSNNMDCSA-N lisinopril Chemical compound C([C@H](N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(O)=O)C(O)=O)CC1=CC=CC=C1 RLAWWYSOJDYHDC-BZSNNMDCSA-N 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 229940064003 local anesthetic throat preparations Drugs 0.000 description 1
- 230000002101 lytic Effects 0.000 description 1
- 201000010230 macular retinal edema Diseases 0.000 description 1
- 239000003628 mammalian target of rapamycin inhibitor Substances 0.000 description 1
- 229960003803 meclofenamic acid Drugs 0.000 description 1
- 229960001474 meclozine Drugs 0.000 description 1
- 229960003464 mefenamic acid Drugs 0.000 description 1
- 229960001924 melphalan Drugs 0.000 description 1
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 1
- 229960001428 mercaptopurine Drugs 0.000 description 1
- JHPHVAVFUYTVCL-UHFFFAOYSA-M methacholine chloride Chemical compound [Cl-].C[N+](C)(C)CC(C)OC(C)=O JHPHVAVFUYTVCL-UHFFFAOYSA-M 0.000 description 1
- TWXDDNPPQUTEOV-FVGYRXGTSA-N methamphetamine hydrochloride Chemical compound Cl.CN[C@@H](C)CC1=CC=CC=C1 TWXDDNPPQUTEOV-FVGYRXGTSA-N 0.000 description 1
- VKQFCGNPDRICFG-UHFFFAOYSA-N methyl 2-methylpropyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCC(C)C)C1C1=CC=CC=C1[N+]([O-])=O VKQFCGNPDRICFG-UHFFFAOYSA-N 0.000 description 1
- JUMYIBMBTDDLNG-UHFFFAOYSA-N methylphenidate hydrochloride Chemical compound [Cl-].C=1C=CC=CC=1C(C(=O)OC)C1CCCC[NH2+]1 JUMYIBMBTDDLNG-UHFFFAOYSA-N 0.000 description 1
- 229960001566 methyltestosterone Drugs 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 238000005459 micromachining Methods 0.000 description 1
- 238000001053 micromoulding Methods 0.000 description 1
- 229960003574 milrinone Drugs 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000006011 modification reaction Methods 0.000 description 1
- 230000000051 modifying Effects 0.000 description 1
- 239000002991 molded plastic Substances 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 230000004118 muscle contraction Effects 0.000 description 1
- 235000010460 mustard Nutrition 0.000 description 1
- 229960004866 mycophenolate mofetil Drugs 0.000 description 1
- 239000003158 myorelaxant agent Substances 0.000 description 1
- BLXXJMDCKKHMKV-UHFFFAOYSA-N nabumeton Chemical compound C1=C(CCC(C)=O)C=CC2=CC(OC)=CC=C21 BLXXJMDCKKHMKV-UHFFFAOYSA-N 0.000 description 1
- 229960004270 nabumetone Drugs 0.000 description 1
- 229960002009 naproxen Drugs 0.000 description 1
- 239000005445 natural product Substances 0.000 description 1
- 229930014626 natural products Natural products 0.000 description 1
- 239000002840 nitric oxide donor Substances 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 229950011191 norgesterone Drugs 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 229940005935 ophthalmologic Antibiotics Drugs 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 210000000056 organs Anatomy 0.000 description 1
- 230000000399 orthopedic Effects 0.000 description 1
- 101700057139 oxyT Proteins 0.000 description 1
- 229940094443 oxytocics Prostaglandins Drugs 0.000 description 1
- 229960005489 paracetamol Drugs 0.000 description 1
- 239000000199 parathyroid hormone Substances 0.000 description 1
- 230000000149 penetrating Effects 0.000 description 1
- 230000000737 periodic Effects 0.000 description 1
- 230000002093 peripheral Effects 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 229960002702 piroxicam Drugs 0.000 description 1
- 239000002373 plant growth inhibitor Substances 0.000 description 1
- 239000000106 platelet aggregation inhibitor Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920002530 poly[4-(4-benzoylphenoxy)phenol] polymer Polymers 0.000 description 1
- 229920000023 polynucleotide Polymers 0.000 description 1
- 239000002157 polynucleotide Substances 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 150000004804 polysaccharides Polymers 0.000 description 1
- 230000002980 postoperative Effects 0.000 description 1
- 230000003389 potentiating Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000002335 preservative Effects 0.000 description 1
- 238000007639 printing Methods 0.000 description 1
- ABTXGJFUQRCPNH-UHFFFAOYSA-N procainamide hydrochloride Chemical compound [H+].[Cl-].CCN(CC)CCNC(=O)C1=CC=C(N)C=C1 ABTXGJFUQRCPNH-UHFFFAOYSA-N 0.000 description 1
- 229960000624 procarbazine Drugs 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 229960003387 progesterone Drugs 0.000 description 1
- 239000000186 progesterone Substances 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 229960003712 propranolol Drugs 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 230000003236 psychic Effects 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 239000003087 receptor blocking agent Substances 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000002829 reduced Effects 0.000 description 1
- 239000003488 releasing hormone Substances 0.000 description 1
- 230000001850 reproductive Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 108010051412 reteplase Proteins 0.000 description 1
- 230000004264 retinal detachment Effects 0.000 description 1
- 150000003872 salicylic acid derivatives Chemical class 0.000 description 1
- 239000004065 semiconductor Substances 0.000 description 1
- 230000001568 sexual Effects 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 231100000185 significant adverse effect Toxicity 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- AGHLUVOCTHWMJV-UHFFFAOYSA-J sodium;gold(3+);2-sulfanylbutanedioate Chemical compound [Na+].[Au+3].[O-]C(=O)CC(S)C([O-])=O.[O-]C(=O)CC(S)C([O-])=O AGHLUVOCTHWMJV-UHFFFAOYSA-J 0.000 description 1
- NHXLMOGPVYXJNR-ATOGVRKGSA-N somatostatin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CSSC[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(=O)N1)[C@@H](C)O)NC(=O)CNC(=O)[C@H](C)N)C(O)=O)=O)[C@H](O)C)C1=CC=CC=C1 NHXLMOGPVYXJNR-ATOGVRKGSA-N 0.000 description 1
- 229960004532 somatropin Drugs 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 229950006904 sulfisoxazole acetyl Drugs 0.000 description 1
- 230000001975 sympathomimetic Effects 0.000 description 1
- 230000000946 synaptic Effects 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 229930003347 taxol Natural products 0.000 description 1
- 210000004876 tela submucosa Anatomy 0.000 description 1
- WZWYJBNHTWCXIM-UHFFFAOYSA-N tenoxicam Chemical compound O=C1C=2SC=CC=2S(=O)(=O)N(C)C1=C(O)NC1=CC=CC=N1 WZWYJBNHTWCXIM-UHFFFAOYSA-N 0.000 description 1
- 229960002871 tenoxicam Drugs 0.000 description 1
- 239000003868 thrombin inhibitor Substances 0.000 description 1
- 230000001646 thyrotropic Effects 0.000 description 1
- 229960004605 timolol Drugs 0.000 description 1
- 200000000020 tissue injury Diseases 0.000 description 1
- 229960000187 tissue plasminogen activator Drugs 0.000 description 1
- 229940083878 topical for treatment of hemorrhoids and anal fissures Corticosteroids Drugs 0.000 description 1
- 230000002936 tranquilizing Effects 0.000 description 1
- 239000003204 tranquilizing agent Substances 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- LXZZYRPGZAFOLE-UHFFFAOYSA-L transplatin Chemical compound [H][N]([H])([H])[Pt](Cl)(Cl)[N]([H])([H])[H] LXZZYRPGZAFOLE-UHFFFAOYSA-L 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 210000000689 upper leg Anatomy 0.000 description 1
- 201000011528 vascular disease Diseases 0.000 description 1
- 229960003726 vasopressin Drugs 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- GBABOYUKABKIAF-IELIFDKJSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-IELIFDKJSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229930003231 vitamins Natural products 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 238000003466 welding Methods 0.000 description 1
- 229960003414 zomepirac Drugs 0.000 description 1
Abstract
A method for making a jet injection drug delivery device wherein the drug delivery device has at least one drug reservoir and at least one injection nozzle includes the steps of:identifying a drug desired to be delivered;identifying a volume of the drug desired to be delivered;establishing a reservoir diameter for the at least one drug reservoir;establishing a nozzle diameter for the at least one injection nozzle;identifying a tissue model for delivery of the drug;identifying a penetration depth in the tissue model for the delivery of the drug;and injecting the drug into the tissue model under variable pressure until the desired penetration depth is achieved. The method also includes identifying an optimal pressure range for the drug delivery device that achieves the desired penetration depth.
Description
METHOD FOR MAKING A DRUG SUPPLY DEVICE THROUGH NO NEEDLE JET INJECTION
FIELD AND BACKGROUND OF THE INVENTION
The present invention relates, in general, to drug delivery and, in particular, to a new and useful device and method for delivering needleless drugs with minimal trauma to tissue and which are suitable for delivering drugs in sensitive areas of the body such as the eyes, nasal passages, mouth and other areas of the body. Despite continuous advances in medical technology, particularly in the treatment of various diseases such as heart disease, vascular disease, ophthalmic disease, cancer, pain, allergies, orthopedic repair and many other diseases and conditions, there is a significant number of patients for who conventional surgery and intervention therapies are not feasible or are insufficient to treat the disease or condition. For many patients, medical treatment with drugs and the like is the only feasible treatment available. There have been many recent advances in drug therapies, particularly with respect to cellular or site-specific therapeutic compounds also known as "local" drug delivery. Unlike the systemic administration of the therapeutic compounds, typically taken orally or given intravenously, much of the effectiveness of local delivery of cellular or site-specific therapeutic drugs or compounds is based on the ability to deliver in an accurate and Accurate the therapeutic compounds to the target site within the body. Needle injection devices are the most commonly used means for local delivery or site-specific administration of agents or solutions. Although there have been advances in needle / injection drug delivery systems, these systems have significant drawbacks and disadvantages. One of those disadvantages is that the use of a needle or other penetrating means to inject the target tissue area inevitably involves making a hole in the target site thus causing trauma and tissue injury at the local tissue site. Another disadvantage with this needle penetration and injection approach is that it is very common for a substantial amount of the injected substance to drain or exude from the hole created by the needle or penetration member. Often, this injected substance that leaks is systematically released throughout the body or is discarded by depriving the patient of the prescribed therapy or dosage amounts of the drug. This also results in increased treatment costs and requires more injections, time and agent to achieve the desired effect. In addition, it is known that needle injections or penetration into tissue can traumatize or destroy tissue cells and, as a result, increase a patient's risk of post-operative trauma, pain and discomfort at the local site and surrounding area. This is particularly due to the difficulty in accurately controlling the penetration of the needle during injection. The more injections or penetrations there are, the greater the cell destruction and tissue trauma that is likely to be experienced. A further disadvantage of needle-based injections, especially where multiple injections are required, is the inability to carefully track the location of each injection site to prevent accidental delivery of drug to non-diseased tissue or repeated delivery of the drug to the same hole. of injection. Other known drug delivery devices and methods do not involve needle-based drug delivery. Instead, devices such as catheters that remain in the interior are used to release the therapeutic agent in a constant controlled release manner. These types of devices could present a higher risk of agent release systematically. furtherWith these types of devices, it is more difficult to evaluate the actual dose of the target area that takes place. Therefore, these types of devices have the disadvantages of being less effective, possibly not as safe, and definitely more expensive than commonly known needle injection approaches and technology. Another condition in which the site or local specific drug supply is commonly used is in the treatment of peripheral vascular disease (such as deep vein thrombosis and embolism). One such treatment is venous lithic therapy, the dissolution of blood clots (thrombi) in the peripheral vasculature (eg, femoral and iliac arteries and veins). The lytic therapy involves the systemic infusion of thrombolytics, such as urokineses, streptokinase, reteplase and tPA. Other more recently developed procedures involve directly supplying the thrombolytics at the site of the thrombus by the use of infusion catheters that remain in the interior. In order to effectively lyse the thrombus, thrombolytics are typically delivered by infusion for many hours, even as many as a day or more, increasing the length of hospital stay and the overall cost of the procedure. A common approach to eliminating a needle in local drug delivery is to use conventional needleless injectors. Needle-free injection technology was introduced almost 40 years ago for use in mass immunization campaigns. Currently, more than fifteen companies develop and manufacture jet injectors for intradermal and transdermal (subcutaneous and intramuscular) drug delivery. And while these modern designs offer tremendous improvements in size, cost and convenience over their predecessors, the fundamental functionality has remained unchanged. Mainly, compressed gas is used to push a medication (either liquid or dry powder) through a single orifice at moderately high speed, allowing the medication to be deposited on or under the skin when piercing it. An example of a known needleless jet injector is described in WO 00/35520 and U.S. Pat. 6,406,455 Bl (Willis et al., Assigned to BioValve Technologies, Inc.). In addition, needleless jet injection has long been considered a painless procedure, but clinical studies comparing injection devices with a conventional needle and syringe have shown pain ratings equivalent to those of a gauge needle. 25. In large part, this is due to the size of the injection stream and, therefore, the size of the nozzle orifice. Existing devices all use a nozzle orifice of approximately 0.15 mm - 0.2 mm in diameter. It is known that these conventional needleless injectors incorporate only one injection chamber and inject the entire drug content through a single plastic nozzle having a typical orifice diameter of 150-200 microns (0.15 mm -0.2 mm). These jet injectors typically deliver volumes ranging from 0.100 cm3 (100 microliters) to 0.500 cm3 (500 microliters), and even as many as 1 cm3 (1,000 microliters). There are several significant limitations with current jet injection technology. First, the injection times associated with these conventional needleless injectors are typically several seconds in duration, which puts the patient at risk of laceration if he moves (e.g., backs off) or if the injector moves in a vibrating manner. of the injection site during an injection. Second, the perceived pain is equivalent to a conventional needle and syringe. This has perhaps been the only important reason why jet injection has not been widely accepted. Third, jet injectors are subject to supplying so-called "wet injections" where the medicine drains back from the injection site, a result that has given rise to concerns about the accuracy of the dose delivered. The first two points, pain and wet injections, are the result of the size of the nozzle orifice (approximately 0.15 mm in current jet injectors). This size resulted in more of the practical limitations of plastic injection molding for high volume commercial manufacture than of any effort in size optimization for user comfort and minimization or elimination of any "leakage" of the injected medicament. . This replacement of sub-optimal performance for manufacturing capacity has resulted in a marginalized product that has not enjoyed market acceptance that it might otherwise have. A particular type of conventional needleless jet is described in the US patent. No. 6,716,190 B1 (Glines et al.) Which teaches a device and methods for the delivery and injection of therapeutic and diagnostic agents to a target site within a body. This device and method uses a complex system comprising a nozzle assembly having an ampoule body and channels milled or machined within the distal surface of the ampoule body. These channels operate as a manifold and are arranged orthogonal to the reservoir orifice. The reservoir orifice ejects or expels the contents that are inside the body of the vial to the orthogonally arranged channels that channel the contents to a plurality of dispersion holes orthogonally disposed to the channels. The dispersion orifices are orthogonal to the channels and are located within the surface facing the target, generally flat distal. Not only is this particular arrangement complex, but it requires high supply pressures for the contents of the ampule in a range of about 126.54 to 351.5 kg / cm2, with some applications in a range of about 126.54 to 161.69 kg / cm2. In addition, the dispersion holes have a diameter of about 0.1 mm to about 0.3 mm (100 to 300 microns). Even when said device does not use a needle, the negative result involved with the use of said device and disposition is that it is likely to cause excessive trauma to the tissue at the delivery site as well as cause unwanted and unnecessary pain and / or discomfort to the tissue. end user or patient due to the high supply pressures required as well as the relatively high size of the dispersion orifices. Accordingly, the device and method of Glines et al. They are not suitable for microjet delivery of drugs especially in sensitive areas of the body such as the eyes, nasal passages and mouth or other sensitive areas of the body, especially those areas that are easily subject to trauma, pain and discomfort. Accordingly, there are a number of sensitive areas in the body and disease states that are extremely difficult to treat using local drug delivery. For example, there are a myriad of ophthalmic diseases that are difficult to treat and the delivery of the drug to the site of disease, i.e., the eyes, is often painful or psychologically uncomfortable for the patient. Relevant examples of these diseases that are extremely difficult to treat include age-related macular degeneration (AMD), diabetic retinopathy, choroidal neovascularization (CNV), macular edema, uveitis and the like. For these types of diseases, systemic drug administration commonly gives subtherapeutic drug concentrations in the eyes and can have significant adverse effects. Consequently, the current treatment for eye diseases often involves direct injection of the medicament into the eyes through a conventional syringe and needle - a painful and undesirable means of delivery to the patient. In addition, chronic treatment requires repeated injections that can result in plaque formations and scarring of the eyes, detachment of the retina and endophthalmitis. As a result of these complications, alternative means of drug delivery to the eyes are being developed. Research areas for delivery include iontophoresis, drug eluting eye implants, photodynamic therapy, "sticky" eye drops, and the like. In addition, it is well established that each of these approaches has its own limitations. For example, iontophoresis has a practical limit to the size of the drug molecule being delivered. One could not expect, for example, to supply molecules with a molecular weight above 20,000 Daltons. However, many new compounds, especially some promising proteins, are all above this size, which vary up to as much as 150,000 Daltons. In addition, eye implants require a surgical procedure for implantation and clarification procedures that are costly, painful, and can result in scarring of the eyes. Implants have the additional limitation of physical size and the amount of drug that can be loaded, or put into the implant. It is also known that photodynamic therapy is an unproven technology whose long-term effects are not understood and can be harmful to the retina. Alternatively, eye drops have long been considered the most convenient (and therefore perceived as the most acceptable) means of delivering drugs to the eyes. The eye drops, however, are washed out of the eyes very quickly and allow only a minimal supply of the contained drug. As a result, "sticky" eye drops, ie eye drops that provide adhesion of the mucosa, have been developed to avoid the "wash" effect, but the rapidity of cell turnover at the surface of the eye is believes that it is limiting in the effectiveness of this means of supply.In addition, the delivery mechanism of the eye drops is passive diffusion through the sclera.In addition, passive diffusion can not deliver drugs with a molecular weight greater than about Moreover, the supply is systemic rather than directed to the eye itself, consequently, there is currently no truly acceptable means of delivering active therapeutic agents to the eyes and other sensitive areas of the body, especially emerging macromolecules that show promise. in the treatment of a variety of ophthalmic diseases and diseases associated with these other sensitive areas of the body. date, there have been no known devices or methods that provide true drug delivery without a needle irrespective of the size of the drug molecules involved and that provide a true drug delivery without a needle with minimal trauma to tissue and that are adequate to deliver drugs in areas sensitive parts of the body such as the eyes, nasal passages or the mouth. To date, there have been no known devices that provide true needleless drug delivery where the devices are microjet delivery devices that are simple and efficient in design and construction, inexpensive and easy to manufacture.
BRIEF DESCRIPTION OF THE INVENTION
The present invention is directed to new and useful devices and methods for supplying needleless drugs with minimal tissue trauma and which are suitable for delivering drugs in sensitive areas of the body such as the eyes, nasal passages, mouth and other areas of the body . Therefore, the present invention is directed to a device for delivering a drug comprising: a housing; at least one nozzle in a portion of the housing; a drug source in the housing; an energy source for providing an impulse pressure of about 56.24 to about 140.6 kg / cm2 to propel the drug through at least one nozzle and out of the housing. In addition, the drug is driven through at least one nozzle within a time ranging from about 10 msec to about 200 msec under activation of the energy source. Moreover, at least one injection nozzle has a diameter ranging from about 10 μm to about 50 μm. In addition, the present invention is also directed to a device for delivering a drug comprising: a supply tube, the delivery tube having a pressure chamber therein; at least one nozzle at a distal end of the supply tube and in fluid communication with the pressure chamber; a drug source adjacent to at least one nozzle; a handle at a proximal end of the supply tube; and an energy source in the handle to provide an impulse pressure of about 56.24 to about 140.6 kg / cm2 to propel the drug through at least one nozzle and supply tube. In addition, the present invention is also directed to a method for making a drug delivery device by jet injection, wherein the drug delivery device has at least one drug reservoir and at least one injection nozzle, in wherein the method comprises the steps of: identifying a drug to be delivered; identify a volume of the drug to be delivered; establishing a reservoir diameter for at least one drug reservoir; establishing a nozzle diameter for at least one injection nozzle; identify a tissue model to deliver the drug; identify a penetration depth in the tissue model for drug delivery; and injecting the drug into the tissue model under variable pressure until the desired depth of penetration is achieved. Moreover, the method further comprises identifying an optimal pressure range for the drug delivery device that achieves the desired depth of penetration. An optimum pressure range for the device according to the present invention is from about 56.24 to about 140.6 kg / cm2 and an optimum pressure range at the tip of at least one injection nozzle for the device of the present invention is from about 281.2 to about 1757.5 kg / cm2. The present invention is also directed to a method for delivering a drug into the tissue comprising the steps of: providing a drug delivery device having at least one nozzle and a drug contained in a portion of the device; identify a site to deliver the drug in or on the tissue; place a portion of the device on or near the site; and delivering the drug into the tissue at the site through at least one nozzle of the device under microjet propulsion at a pulse pressure of about 56.24 to about 140.6 kg / cm2. The method further comprises delivering the drug into the tissue at the site with a tip pressure of at least one nozzle ranging from about 281.2 to about 1757.5 kg / cm2.
BRIEF DESCRIPTION OF THE DRAWINGS
The novel features of the invention are set forth with particularity in the appended claims. The invention itself, however, in terms of organization and methods of operation, together with additional objects and advantages thereof; can be understood by reference to the following description, taken in conjunction with the accompanying drawings in which: Figure 1 is a perspective view of one embodiment of a microjet drug delivery device in accordance with the present invention; Figure 2 is an exploded view of the device of Figure 1 according to the present invention; Figure 3 is a cross-sectional view of the device of Figure 1 in a pre-triggered configuration in accordance with the present invention; Figure 4 is a cross-sectional view of the device of Figure 1 in a fired configuration in accordance with the present invention; Figure 5 is a proximal perspective view of another embodiment of a drug delivery device per microjet particularly useful for applications such as ocular use in accordance with the present invention; Figure 6 is a distal perspective view of the device of Figure 5 in accordance with the present invention; Figure 7A is a cross-sectional view of the device of Figure 5 in accordance with the present invention; Figure 7B is a cross-sectional view of an alternative embodiment of the device of Figure 7A having an LED focusing light in accordance with the present invention; Figure 8 is a partial cross-sectional side view of another embodiment of a drug delivery device per microjet particularly useful for applications such as nasal use in accordance with the present invention; Fig. 9 is an enlarged partial side view of the distal end of the device of Fig. 8 in accordance with the present invention; Figure 10 is an illustration of the device in Figure 8 during use for a nasal application in accordance with the present invention; and Figure 11 is a graph illustrating a penetration depth versus pressure study for the drug delivery device per microjet having a 50 μm diameter and nozzle and 100 μl drug delivery volume in accordance with the present invention.
DESCRIPTION OF THE PREFERRED MODALITIES
The present invention addresses novel drug delivery devices, their methods of manufacture and their methods of use. As best shown in Figs. 1-10, the present invention is a needle-free (needle-free), 20a drug microjet device 20 delivery device.
20b, its manufacturing methods and its methods of use, which are all elaborated in more detail later. The drug delivery device 20, 20a and 20b, in accordance with the present invention is a needleless jet injection device that delivers drugs, such as liquid drug formulations, to a patient by injecting very fine streams of the formulations of high-speed drug The drug delivery device 20, 20a and 20b provides a less painful means of administering drugs than conventional needle and syringe devices as well as known needleless injection devices. The drug delivery device 20, 20a and 20b, in accordance with the present invention, can be used in a variety of medical applications, including transdermal, dermal, infraocular, intranasal, oral, and generally transmucosal drug delivery. The terms "drug delivery device", "delivery device", "needleless drug delivery device", "needleless microjet drug delivery device", "drug delivery device per microjet", "device Needleless Drug Delivery "," Needleless Microjet Drug Delivery Device ", "needleless jet injection device", "needle free jet injection device", "jet injection device", "microjet device" and "microjet", including various combinations of any parts of these terms, they all intend to have the same meaning and are used interchangeably here. The terms "active agent formulation" and "drug formulation" and "formulation" mean the drug or active agent optionally in combination with pharmaceutically acceptable carriers and additional inert ingredients. The formulation can be either solid, liquid or semi-solid or semi-liquid or combinations thereof. The terms "drug", "agent", active agent "and" pharmaceutical composition "are used interchangeably herein and refer to an agent, drug, compound, material composition or mixture thereof, including its formulation, which provides some therapeutic effect , often beneficial, this includes pesticides, herbicides, germicides, biocides, algicides, rodenticjdas, fungicides, insecticides, antioxidants, plant growth promoters, plant growth inhibitors, preservatives, anti-preservatives, disinfectants, sterilization agents, catalysts , chemical reagents, fermentation agents, food, food supplements, nutrients, cosmetics, drugs, vitamins, sexual sterilizers, fertility inhibitors, fertility promoters, attenuators of microorganisms and other agents that benefit the environment of use. the terms also include any substance physiologically or pharmacologically and active that produces a localized or systemic effect or effects in animals, including warm-blooded mammals, humans and primates; birds; domestic or farm animals such as cats, dogs, sheep, goats, cattle, horses and pigs; laboratory animals such as mice, rats and guinea pigs; fishes; reptiles; zoo and wild animals; and similar. The active drug that can be supplied includes inorganic and organic compounds, including, without limitation, drugs that act on the peripheral nerves, adrenergic receptors, cholinergic receptors, skeletal muscles, the cardiovascular system, smooth muscles, the blood circulatory system, synaptic sites , neuroefector binding sites, endocrine and hormonal systems, the innmunological system, the reproductive system, the skeletal system, the autacoid systems, the food and excretory systems, the histamine system and the central nervous system. Suitable agents can be selected, for example, from proteins, enzymes, hormones, polynucleotides, nucleoproteins, polysaccharides, glycoproteins, lipoproteins, polypeptides, spheroids, hypnotics and sedatives, psychic energizers, tranquilizers, anticonvulsants, muscle relaxants, antiparkinson agents, analgesics, anti -inflammatories, local anesthetics, muscular contraction agents, antimicrobial agents, antimalarials, hormonal agents including contraceptives, sympathomimetics, polypeptides and proteins capable of inducing physiological effects, diuretics, lipid regulating agents, antiandrogenic agents, antiparasitic agents, neoplasms, antineoplastics, hypoglycemics, agents and nutritional supplements, growth supplements, fats, ophthalmic agents, antiteteritis agents, electrolytes and diagnostic agents. Examples of drugs or agents useful in this invention include prochlorperazine edisylate, ferrous sulfate, aminocaproic acid, mechaxylamine hydrochloride, procainamide hydrochloride, amphetamine sulfate, methamphetamine hydrochloride, benzfetamine hydrochloride, isoproteronol sulfate, phenmetrazine hydrochloride, betanecol, methacholine chloride, pilocarpine hydrochloride, atropine sulfate, scopolamine bromide, isopropamide iodide, tridihexetil chloride, fenformin hydrochloride, methylphenidate hydrochloride, theophylline kohlrabi, cephalexin hydrochloride, diphenidol, meclizine hydrochloride, maleate prochlorperazine, phenoxybenzamine, maleate of thiethylperazine, anisindione, diphenadione, erythritil tetranitrate, digoxin, soflurofato, acetazolamide, methazolamide, bendroflumetiazide, chlorpropamide, tolazamide, chlormadinone acetate, phenaglycodol, allopurinol, aluminum aspirin, methotrexate, acetyl sulfisoxazole, hydrocortisone, aceta hydrocorticosterone, cortisone acetate, dexamethasone and its derivatives such as betamethasone, triamcinolone, methyltestosterone, 17-beta-estradiol, ethinyl estradiol, ethinylestradiol 3-methyl ether, prednisolone, 17-beta-hydroxyprogesterone acetate, 19-nor- progesterone, norgestrel, norethindrone, norethisterone, noretiederone, progesterone, norgesterone, norethynodrel, indomethacin, naproxen, fenoprofen, sulindac, indoprofen, nitroglycerin, isosorbide dinitrate, propranolol, timolol, atenolol, alprenolol, cimetidine, clonidine, imipramine, levodopa, chlorpromazine, methyldopa, dihydroxyphenylalanine, theophylline, calcium gluconate, ketoprofen, ibuprofen, cephalexin, erythromycin, haloperidol, zomepirac, ferrous lactate, vincamine, phenoxybenzamine, diltiazem, milrinone, captropril, mandol, quanbenz, hydrochlorothiazide, ranitidine, flurbiprofen, fenbufen, fluprofen, tolmetin , alclofenac, mefenamic, flufenamic, difuninal, nimodipine, nitrendipine, nisoldipine, nicardipine, f elodipine, lidoflazine, thiaparil, gallopamil, amlodipine, myoflazine, lisinopril, enalapril, captopril, ramipril, enalaprilat, famotidine, nizatidine, sucralfate, etintidine, tetratolol, minoxidil, chlordiazepoxide, diazepam, arnitriptilin and imipramine. Further examples are proteins and peptides including, but not limited to, insulin, colchicine, glucagon, thyroid stimulating hormone, parathyroid and pituitary hormones, calcitonin, renin, prolactin, corticotrophin, thyrotropic hormone, follicle-stimulating hormone, chorionic gonadotropin, gonadotropin-releasing hormone, bovine somatotropin, somatropin porcine, oxytocin, vasopressin, prolactin, somatostatin, lyserin, pancreozimine, luteinizing hormone, LHRH, interferons, interleukins, growth hormones such as human growth hormone, bovine growth hormone and porcine growth hormone, fertility inhibitors such as prostaglandins, fertility promoters, growth factors, human pancreatic releasing factor, antiproliferative / antimitotic agents including natural products such as vinca alkaloids (ie, vinblastine, vincristine and vinorelbine), paclitaxel, epidipodophyllotoxins (ie, etoposide, teniposide), antibiotics (dactinomycin (a cynomycin D) daunorubicin, doxorubicin and idarubicin), anthracyclines, mitoxantrone, bleomycins, plicamycin (mitramycin) and mitomycin, enzymes (L-asparaginase that systematically metabolizes L-asparagine and deprives cells that do not have the ability to synthesize their own asparagine); antiplatelet agents such as inhibitors of G (GP) lllla and vitronectin receptor antagonists; antiproliferative / antimitotic alkylating agents such as nitrogenous mustards (mechlorethamine, cyclophosphamide and the like, melphalan, chlorambucil), ethyleneimines and methylmelamines (hexamethylmelamine and thiotepa), alkyl sulfonates-busulfan, nirtosoureas (carmustine (BCNU) and the like, streptozocin), trazenos- Dacarbazinin (DTIC); antiproliferative / antimitotic antimetabolites such as folic acid analogs (methotrexate), pyrimidine analogues (fluorouracil, floxuridine and cytarabine), purine analogues and related inhibitors (mercaptopurine, thioguanine, pentostatin and 2-chlorodeoxyadenosine., cladribine.); platinum coordination complexes (cisplatin, carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide; hormones (ie, estrogen); anticoagulants (heparin, synthetic heparin salts and other thrombin inhibitors); fibrinolytic agents (such as tissue plasminogen activator, streptokinase and urokinase), aspirin, dipyridamole, ticlopidine, clopidogrel, abciximab; anti-migratory; antisecretor (breveldin); antiinflammatories: such as adrenocortical steroids (cortisol, cortisone, hydrocortisone, prednisone, prednisolone, 6a-methylprednisolone, triamcinolone, betamethasone, and dexamethasone), non-steroidal agents (salicylic acid derivatives, ie, aspirin; para-aminophenol derivatives; say, acetaminophen, indole and indenacetic acids (indomethacin, sulindac and etodalac), heteroaryl acetic acids (tolmetin, diclofenac and ketorolac), arylpropionic acids (ibuprofen and derivatives), anthranilic acids (mefenamic acid, and meclofenamic acid), enolic acids (piroxicam) , tenoxicam, phenylbutazone and oxifentatrazone), nabumetone, gold compounds (auranofin, aurothioglucose, gold thiomalate sodium), immunosuppressants: (cyclosporine, tacrolimus (FK-506), sirolimus (rapamycin), azathioprine, mycophenolate mofetil), angiogenic agents : vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), growth factor derived from platelets (PDGF), erythropoietin; angiotensin receptor blocker; nitric oxide donors; antisense oligonucleotides and combinations thereof; cell cycle inhibitors, mTOR inhibitors, kinase inhibitors of growth factor signal transduction, chemical compound, biological molecule, nucleic acids such as DNA and RNA, amino acids, peptide, protein or combinations thereof. It should be understood that more than one drug or agent can be combined or mixed together and incorporated into or used by the present invention, and that the use of the term "drug", "agent" or "drug" or
"Pharmaceutical composition" in no way excludes the use of two or more of those drugs, agents, active agents and / or pharmaceutical compositions. One embodiment of the drug delivery device 20 in accordance with the present invention is illustrated in Figures 1-4. The drug delivery device 20 is a needleless jet injection device especially useful for injecting drug delivered under microjet thrust in very fine streams at high speed in various types of body tissue, including organs. By way of example, the drug delivery device 20 in accordance with the present invention is particularly useful for the dermal or transdermal delivery of drugs to a patient, i.e., as a dermal or transdermal drug delivery device for delivering drugs without a needle to the various layers of skin or through the layers of skin and to the bloodstream and circulatory system of the patient. While the drug delivery device 20, in accordance with the present invention, is not limited to dermal and transdermal applications, rather, it is intended to be used for other types of tissue and other medical, therapeutic and diagnostic applications. The drug delivery device 20 has a housing 24 and a cover 28 at a proximal end of the housing 24 and a nozzle plate 30 at the distal end of the housing 24. One or more nozzles 34 or a plurality of nozzles 34, which are Jet injection nozzles (also referred to as "micro-nozzles"), are disposed on the nozzle plate 30. As shown in FIGS. 1-4, the injection nozzles 34 terminate as small projecting projections from the outer surface of the nozzle plate 30 thus providing the user with tactile feedback for the proper location and arrangement of the injection nozzles 34 on the user's tissue surface. As best illustrated in Figures 2, 3 and 4, housing 24 further includes one or more reservoirs 38 aligned and in fluid communication with one or more nozzles 34. Each reservoir 38 is longitudinally disposed in housing 24 and serves as a reservoir. drug reservoir or storage space for the drug 40. Each reservoir is configured to receive a push bar 48 and a reservoir seal 54 attached or attached to the distal end of each push bar 48. The push bar 48 and seal of reservoir 54 are in direct longitudinal alignment with each reservoir 38 and push bar 48 and reservoir seal are movably (longitudinally movable) within each drug reservoir 38. Each reservoir seal 54 is designed to prevent the drug 40 leaches or drips from the drug reservoir 38. Therefore, the reservoir seal 54 is in movable sealable contact with the inner wall of the drug reservoir 38. The push bar 48 and the reservoir seal 54 are slidably movable longitudinally in each reservoir 38. The piston 44 is integral to or attached to the proximal end of each push bar 48 and serves as a pulse platform for accumulating and exerting a force of pushing the push rods 48. The piston 44 can be fixed as an individual unit to the proximal end of all the push rods 48 in order to operate and move each push rod 48 simultaneously within each reservoir 38 or the piston 44 it can be fixed to the proximal end of each push bar 48 individually in order to operate selectively and individually and move each push bar 48 within the reservoir 38. In this example, the piston 44 has a cylindrical shape configured to fit securely within and in movable hitch with the inner wall of the housing 24 which also has a cylindrical shape. The piston 44 has a circumferential space configured to receive an O-ring seal 52 which is also configured to fit securely within and in movable engagement with the inner wall of the housing 24 together with the piston 44. The seal 52 can be any type of seal whenever you prevent the gas, discharge content or other material is leach or penetrate beyond the piston 44. As best shown in Figure 3 (drug delivery device 20 loaded with the drug 40 and in its predisposed configuration), a power source to discharge A driving force to the piston 44 is located proximal to or greater than the piston 44 within the housing 24, for example, in an embodiment in accordance with the present invention, a load housing 60 located in the proximal or upper portion of the housing 24. The load pyrotechnic 64 is contained within the loading housing 60. A detonator 68 is located adjacent the pyrotechnic charge 64 to contain a small explosive charge that delivers pyrotechnic energy or ignition energy to the pyrotechnic charge 64 to ignite the pyrotechnic charge 64 upon activation of the detonator 68. A blow pin 70 is located in the cover 28 and movably engages or movably contacts with the toner 68 for activating the detonator 68 and initiating the explosive charge contained in the detonator 68. The hit pin 70 is movably connected to an activation element such as an activation button 74 that is movably deflected by the spring 72. Therefore, , the activation button is movably diverted to the strike pin 70 within the cover 28 to urge the strike pin 70 towards the detonator 70 under a sufficient downward force pressed on the activation button 74, for example, by the user's thumb or patient. As best shown in Figure 4 (drug delivery device 20 in its fired configuration after having injected drug 40 under microjet propulsion), by depressing the activation button 74, the hit pin 70 hits the detonator 68 thus activating the detonator 68, which in turn causes the extremely rapid combustion of a pyrotechnic charge 64. This controlled explosion provides the driving force necessary to slidably advance the piston 44 and the fixed thrust rods 48 through the reservoirs 48 that make that the push bars 48 are ejected by drug microjet propulsion 40 outwardly through the injection nozzles 34. The energy source, such as pyrotechnic charge 64 or compressed gas 36 (FIGS. 8 and 10) supplies sufficient energy and pulse pressure to maintain the pulse piston 44 and associated push rods 48 ranging from about 56.24 to about 140. 6 kg / cm2. In turn, the energy and pressure at the tips of the micro nozzles 34 vary from about 281.2 to about 1757.5 kg / cm2 at each microtitre tip, and preferably in the range from about 562.4 to about 843.6 kg / cm2 at each microtitre tip and most preferably at about 703 kg / cm2 in each microtitre tip. For all embodiments of the present invention, the same number of references are used to designate the same or similar features and parts. Accordingly, Figures 5, 6, 7A and 7B, illustrate another embodiment of the present invention that is particularly useful for ophthalmic and ocular applications such as drug delivery 40 to the eyes of a patient 100. Therefore, the nozzle 30a at the distal end of the housing 24 has a contoured distal end 31 which is a concave ring having an opening in a central portion thereof. In this example, the contoured distal end 31 has a plurality of injection nozzles 34 circumferentially disposed within the contour (concave region) defined by the contoured distal end 31 and spaced proximally at a distance away from the edge of the outer surface of the circumference outer (periphery or outer edge) of the contoured distal end 31. Accordingly, in this example, the nozzle plate 30a having a contoured distal end 31 is configured to receive an eye of a patient 100 wherein the pupil of the eye 100 can be located within the central portion (open space) of the circumferential ring of the contoured distal end 31. Therefore, if desired, the drug 40 can be delivered under microjet propulsion to areas of the eye 100 outside the pupil, such as the vitreous or sclera, as best shown in Figure 5. Figure 7B illustrates an alternative embodiment of the invention. drug delivery device 20a wherein a cavity of the light emitting diode (LED) 76 is provided in the central portion (open space) of the circumferential ring of the contoured distal end 31 of the nozzle plate 30a. An LED 80 is located in the LED cavity 76 to disperse a focus light (focus LED light) 88 under operational control from the switch 86 movably located in an outer portion of the housing 24 in this example near the proximal end of the housing 24). Switch 86 serves as a power switch for activating LED 80 to project focus light 88, i.e. switch 86 serves as an "on", "off" switch for LED 80 and light 88. For purposes of Briefly, the contacts, terminals and cables that operatively connect the LED 80 to the switch 86 are not shown, but are well understood and can be appreciated by an expert in the field. The focus light 88 is used to attract the direct attention of the patient, align and focus the pupil of the eye 100 and serves as a focal point of attention by the patient in order to mentally relax the patient (basically distract the patient) while the drug 40 is supplied to the eye 100 under microjet propulsion. Therefore, the LED 80 and the focus light 88 serve as a means to reduce the levels of stress in the patient and the anxiety normally associated with receiving a drug injection, particularly in a sensitive area such as the eye 100. Alternatively, instead of an LED 80, an element or feature that is luminescent (including self-luminescent) or an element or feature having a luminescent coating, such as a point having luminescent coating that is used as a focal point and can be used to attract the direct attention of the patient and focus of the pupil of the eye 100 to serve as a focal point of patient care in order to mentally relax the patient in anticipation of and while receiving the injected drug 40 under microjet propulsion. A point coated with tritium is one of these suitable substitutes as an example. Figures 8, 9 and 10 illustrate another embodiment of the present invention wherein the drug delivery device 20b uses an elongated cylindrical tube as a delivery tube 25 having a pressure chamber 27 therein. A handle 23 is connected to the supply tube 25 at a proximal portion of the supply tube 25. A valve 33 is connected to the proximal end of the supply tube 25 and pressure chamber 27 and a source of compressed gas 36, such as C02 gas compressed contained in a cartridge 36 and is connected to another end to the valve 33 and contained within the handle 23. The cartridge 36 is a miniature compressed gas cylinder containing a compressed gas such as C02 with the ability to achieve and supply pressures as high as 140.6 kg / cm2. The valve 33 regulates the release of compressed gas from the cartridge 23 into the pressure chamber 27 of the supply tube 25 by activating the button 74a located at a convenient location on the handle 23, for example, easily accessible with the index finger of the hand of the patient or user. If desired, a detachably connected cover (not shown) can be used with a handle 23 to provide direct access to the gas cartridge 36 to exchange the cartridge 36 after its contents are spent (when empty) with a gas cartridge newly loaded (complete) 36 thereby making the drug delivery device 20b a multi-use device or reusable device. As shown in Figure 9, the nozzle plate 30 and the nozzles 34 are located at the distal end of the supply tube 25 and pressure chamber 27 and are arranged as projections extending outward from the outer surface of the plate. of nozzle 30 to provide the user 90 with tactile feedback for proper location and alignment of the injection nozzles 34 on a tissue surface of the user's body, for example, on the tissue located within a nostril of the nose 110 (as shown in FIG. 10) or tissue located inside the mouth of the patient (buccal application), such as the gums or palate of the mouth, or a place inside the patient's ear, etc. Therefore, the drug delivery device 20b is suitable for delivering drug 40 to areas difficult to access from the patient's body due to the design of the elongate and low profile. The drug reservoirs 38, the drug 40, reservoir seals 54, push rods 48, piston 44 and O-ring 52 are arranged and operate in the same manner or in a manner similar to that described for the embodiments of FIGS. 7B, except that these features are located within the supply tube 25 and pressure chamber 27 at the distal end of the supply tube 25 and pressure chamber 27. The pressure chamber 27 allows the compressed gas to be released from the cartridge 36 and it channels the gas from the handle 23 to the piston 44 along the entire length of the supply pipe 25 which provides the driving force necessary to slidably advance the piston 44 and the fixed thrust rods 48 through the tanks 48. causing the push bars 48 to eject the drug 40 outwardly through the injection nozzles 34. The drug delivery device 20 (FIGS. 1-4), 20a (FIG. uras 5, 6, 7A and 7B) and 20b (Figures 8-10) are designed to be compact in design, for example, having exterior surface dimensions that measure approximately 5.08 cm in length and 1.52 cm in diameter (for the modes of Figures 1-4 and Figures 5, 6, 7A and 7B respectively), and of very light weight, for example weighing only a few grams. Ergonomically, it may be desirable to increase the size or change the geometry significantly, but the fundamental functionality remains exactly the same as that presented in these figures. Alternatively, the power source for discharging a pulse force to the piston 44 is compressed gas, such as C02 as an example, releasably housed in a gas cartridge 36 (Figure 8). Moreover, the energy source for discharging a pulse force to the piston 44 can be any type of energy force as long as it is capable of delivering drug under microjet propulsion in accordance with the requirements set forth below and later in the description. For example, the energy source must discharge sufficient broad energy in order to drive the main pulse piston 44 and associated thrust rods 48 at a pulse pressure ranging from about 56.24 to about 140.6 kg / cm2. In turn, the energy and force at the tips of the micro nozzles 34 vary from about 281.2 to about 1757.5 kg / cm2 at each microtitre tip and preferably at a range from about 561.4 to about 843.6 kg / cm2 at each microtitre tip, and most preferably at about 703 kg / cm2 in each microtitre tip. The volume of the drug 40 delivered under microjet thrust by the drug delivery device 20 (Figures 1-4) 20a (Figures 5, 6, 7A and 7B) and 20b (Figures 8-10), in accordance with the present invention , it is customized, adjustable and variable in order to accommodate the supply of any type of drug, any type of tissue and any type of medical application. The volumes of drug delivered can be adjusted according to a volume range that is from about 10 microliters (μl) or less to about 1 milliliter (mi) or more depending on the configuration or design of the drug delivery device 20, 20a and 20b. In addition, the diameter of the injection nozzle (s) 34 is variable and varies from about 10 (μm) to about 50 (μm) or more, giving exceptionally fine injection currents of drug 40 and minimizing the number of nerve receptors impacted by an injection thus reducing the trauma, pain and discomfort for the patient. One aspect of the novelty and uniqueness of the drug delivery device 20 (Figures 1-4) 20a (Figures 5, 6, 7A and 7B) and 20b (Figures 8-10), in accordance with the present invention is its use of one or more discrete drug reservoirs 38 that serve as injection chambers wherein each reservoir contains drug 40 as a portion of the total injection volume of the total dose for drug 40 as best shown in FIG. 3 (delivery device). drug 20 shown in its predispared configuration before delivering drug 40). In addition, each reservoir 38 has its own dedicated injection nozzle 34 of extremely small diameter. For example, the diameter of each nozzle 34 ranges from about 10 μm to about 50 microns. Therefore, the drug delivery device 20 (Figs. 1-4) 20a (Figs. 5, 6, 7a and 7B) and 20b (Figs. 8-10), in accordance with the present invention divides the total delivery volume for the drug 40 in and through multiple discrete reservoirs 38 (for those embodiments in accordance with the present invention having more than one injection reservoir 38), and supplying each volume of drug contained therein in the patient's tissue at higher speeds as best shown in Figure 4 (drug delivery device 20 shown in fired configuration after delivering drug 40 under microjet propulsion) than those injection rates achieved with conventional jet injectors such as those jet injectors delineated above. Accordingly, an advantage associated with drug delivery device 20 (Figs. 1-4), 20a (Figs. 5, 6, 7A and 7B) and 20b (Figs. 8-10) in accordance with the present invention is a drastic decrease in the time required to inject drug 40 where this time can be as short as 40 milliseconds (msec). Even for a requirement for the delivery of 0.5 cm3 (or 0.5 ml) drug injection 40, the injection time achieved by the drug delivery device 20 (figures 1-4), 20a (figures 5, 6, 7A and 7B) ) and 20b (Figures 8-10) ranges from about 10 msec to about 200 msec (and, in one example, ranges from about 40 msec to about 100 msec for about 0.5 mL of certain types of drugs). A further aspect of the present invention is that since the area of the jet stream decreases with the diameter frame, there is almost a 100-fold reduction in the area of skin or tissue affected by injection with a drug delivery device. 20 (figures 1-4), 20a (figures 5, 6, 7A and 7B) and 20b (figures 8-10) as compared to the known thinner conventional hypodermic needle (ultrafine insulin needle having a 31-gauge cannula) with a diameter of 0.6 mm). In one embodiment in accordance with the present invention, the drug delivery device 20 (Figure 1-4), 20a (Figure 5, 6, 7A and 7B) and 20b (Figure 8-10) is a drug delivery device. pre-filled, single-use (designed to be used once as a disposable unit, ie, a single use, once, by the patient) that does not require preparation or adjustment in advance by the patient's care provider. Therefore, the drug delivery device 20 (Figures 1-4), 20a (Figures 5, 6, 7A and 7B) and 20b (Figures 8-10) is ready to be used as manufactured and is provided. Alternatively, the drug delivery device 20 (Figs. 1-4), 20a (Figs. 5, 6, 7A and 7B) and 20b (Figs. 8-10) is also intended to be a reusable unit (e.g., the main housing 24). , lid 28 with activation button 74 and supply tube 25 and handle 23 with activation button 74a would be reused and resterilized if required) with a single use, disposable internal assembly that is either refilled or reloaded by the patient or provider of health care before administration, inserted into the housing 24 or handle 23 and supply tube 25 (for the drug delivery device 20b) and then removed and discarded after use. In this case, the disposable internal assembly comprises a detonator 68, pyrotechnic charge 64 (or compressed gas cylinder 36), push bars of the drug reservoir 48, drug reservoirs 38, injection nozzles 34. the reusable housing 24 and tube of supply 25 and handle 23 and other components such as cover 28 and activation buttons 74 and 74a are made of a suitable material such as metal or metal alloy capable of resisting reuse and sterilization again if necessary. Furthermore, in all embodiments of the present invention, the injection nozzles 34 may be in the form of an arrangement of injection nozzles 34 (in any desired pattern on the nozzle plate 30 and 30a) that are configured out of the plane or at different angles. of the trajectory, for example, in order to provide objective convergence of the drug 40 either to a particular target point in the tissue, i.e., a single target point in the tissue to receive the entire volume of injected drug 40 or a plurality of of desired target points in the fabric.
Optimization of Drug Delivery by Microjet Propulsion and Manufacturing Method There are two mechanisms that are used to characterize and measure the performance of the drug delivery device 20 (Figures 1-4), 20a (Figures 5, 6, 7A and 7B) and 20b (Figures 8-10) in accordance with the present invention. The first mechanism is a predictive model based on the so-called Hagen-Pouiselle equation. This equation was used to estimate the effects of different designs on the main elements and components of the drug delivery device 20 (figures 1-4), 20a (figures 5, 6, 7A and 7B) and 20b (figures 8-10) and its methods of use and the resulting driving forces required to operate the drug delivery device in accordance with the performance criteria of the present invention. In addition, the actual forces required for drug delivery amounts required under microjet propulsion were determined empirically through both in vitro and in vivo tests.
For example, Figure 11 is a graph depicting the findings of one of these relevant in vitro studies used to determine penetration depth versus pressure for the drug delivery device per microjet (20, 20a and 20b) having nozzle diameter. of 50 μm and volume of drug supplied of 100 μl according to the present invention. During the development and manufacture of the drug delivery device 20, 20a and 20b according to the present invention, there is a force / volume / length exchange based on the diameter of the individual drug reservoirs 38, as well as the diameters of the injection nozzles 34 and the desired injection rate or mass flow rate of drug 40 or drug formulation 40 ejected. In addition, the design of these components has implications for the duration of the injection, the number of drug reservoirs 38 and injection nozzles 34 that are used, the size of the main piston 44 and even the physical properties required by the construction materials for many of the key elements of the drug delivery device 20, 20a and 20b. This relation is modeled by the Hagen-Pouiselle equation as follows: F = 8QμL (R2 / r4) where: F = Injection force Q = Flow rate of the formulation or drug injectable material μ = viscosity of the formulation or injectable drug material L = Injection nozzle length R = Drug reservoir radius r = injection nozzle radius To demonstrate the utility of this equation, suppose you want to supply 500 microliters (1/2 cm3) of a formulation of aqueous drug 40 (a drug solution 40 with viscosity = 1 cps) to the subcutaneous layer of tissue at a flow rate Q of 5 cm3 / second. Also, suppose that a microtiter diameter or injection nozzle of 50 microns, or r = 25 microns, is being used. Although the length of the drug reservoir is to be minimized, it is also desired to minimize the injection force. Therefore, although the shorter length is better, the smaller diameter also means less force but a longer length. Therefore, a convenient size is selected with respect to a suitable reservoir length for a portable microjet device delivery device (20, 20a and 20b) while also attempting to minimize injection force. Consequently, drug deposits of 1.82 mm in diameter, or 0.914 mm of R. were selected.
L of the injection nozzle 34 is determined by construction constraints (a very small hole can only be made in a given material for a limited length). Therefore, it is assumed that an adequate length L is 1.27 mm. Therefore, the Hagen-Pouiselle equation can estimate the injection force required for any injection nozzle given as follows: Con: Q = 5 cm3 / sec μ = 1 cps L = 0.127 cm R = 0.091 cm r = 0.0025 cm F = 8QμL (R2 / r4) = 10, 218,121 dynes or approximately 10.44 kgf. The number of drug reservoirs 38 is determined by the total force that the main impulse piston 44 can exert divided by the force required to propel each of the reservoir thrust rods of 48 which act as individual pistons simultaneously in this example ( expressed as an integer). The practical pressure achieved either by the pyrotechnic charge 64 or a cylinder of compressed gas 36 is limited to approximately 140.6 kg / cm2. Consequently, given a main piston 44 of 1.27 cm and the resulting area of (0.635 cm) 2 times pi = 1.26 cm2, the maximum available impulse force is 140.6 kg / cm2 x 1.26 cm2 or 177.9 kg of force. With 10.44 kg of force required to drive each drug reservoir push bar 48 and 177.9 kg of available force, the maximum number of drug reservoirs 38 that can be accommodated (as an integer) is 177.9 divided by 10.44 or a total of seventeen (17) reservoirs 38. The length of each drug reservoir 38 is calculated as a result of the volume requirement for each. For example purposes, assume that five (5) deposits are used. Therefore, since it is required that a total of 500 microliters be delivered through the five (5) reservoirs 38, each reservoir 38 will supply 100 microliters of drug 40. Given a reservoir diameter of 1.83 mm, each reservoir length will be 100 microliters divided between the deposit area (pi x (.914 mm) 2) or 38.1 mm in length. In addition, the injection flow rate Q has already been defined as 5 + cm3 / sec (as delineated above). Consequently, the total injection time is determined by the time required to inject the volume of drug contained within each individual reservoir 38, which has been found to be 100 microliters or 1 / 10a of cm3. Therefore, the injection time is 0.1 Ocm3 by the reciprocal of the flow regime Q or 20 milliseconds. As a predictive model, the Hagen-Pouiselle equation is a useful tool for preliminary and predictive analysis of design parameters required for elements of the drug delivery device 20, 20a and 20b, but as would be expected, the empirical findings did not differ from the predictive analysis Both in in vitro tests that included the use of a 2 mm thick ballistic gelatin on a Pluronic solution (FI27) and in vivo tests that included testing of the drug delivery device according to the present invention in the The hairless guinea pig model demonstrated that the drug formulation 40 is required to be pressurized to approximately 140.6 kg / cm2 in order to achieve microjet propulsion, ie, the speeds necessary for the drug formulation 40 to be delivered through the injection nozzles 34 at a depth of penetration into the tissue, such as the skin, necessary for therapeutic administration, i.e., in this case, subcutaneous administration. Given, for example, that the drug reservoir 38 has a diameter of 1.8 mm, the cross-sectional area of each drug reservoir 38 is (0.914) 2 per pi or 0.018 cm 2. With the force F equal to the pressure P for the area A, the force necessary to drive the push bars 48 to achieve a pressure of 562.4 kg / cm2 in the drug formulation 40 is 8,000 times 0.004 or 14.52 kg of force. This was a moderate increase over the 10.44 kg of force predicted by Hagen-Pouiselle, but certainly along the same order of magnitude. Much of the increase is explained by the friction of the sliding reservoir seals 54 and O-ring 52. Continuing with the values used in the example for the Hagen-Pouiselle equation, assuming that 500 microliters of drug formulation 40 are required for total administration and five (5) drug reservoirs 38 are being used for the design, then each reservoir 38 contains 500/5 or 100 microliters of drug formulation 40. Within 14.52 kg of force required for each drug reservoir 38 and five total drug deposits, it was calculated that 14.52 x 5 or 72.64 kg of total force is needed to drive all the push bars of the drug reservoir 48. Therefore, the main driver piston 44 must exert a force of 72.64 kg. Given a diameter of 1.27 cm for the main impulse piston 44 (note that this dimension can be higher or lower depending on the application and practical ergonomic limitations of physical size), the piston area 44 is (0.635 cm) 2 by pi or 0.497 cm. Therefore, the power source must apply a pressure of F / A (72.64 / 0.497) or 57.36 kg / cm2 to the main drive piston 44. This pressure requirement is within the performance specifications either of a pyrotechnic load 64 or a source of compressed miniature gas 36. The lengths of the drug reservoir 38 and the injection duration will be the same as those given in the Hagen-Pouiselle example. The main drive piston assembly 44 acts as an accumulator for the pressure generated by the pyrotechnic charge 64 as shown in Figures 2, 3, 7A and 7B (or, alternatively, a source of compressed gas 36 as shown in the figures 8 and 10), distributing the pressure and translating it as a driving force to the individual push rods 48. The push rods 48 are integral to the main drive piston 44, whereby the total load applied to the piston 44 is transferred proportionally to each of the push bars 48. In the event that a larger size main piston diameter is required, this will result in a greater exerted force for any given machine pressure. For example, if the main piston diameter is increased in the above examples from 1.27 cm to 1.5 cm, then the resultant force of a maximum machine pressure of 140.6 kg / cm2 will increase from 140.6 kg / cm2 x 1.26 cm2 = 177.9 kg of force 140.6 kg / cm2 x 1.82 cm2 = 39.72 kg of force. This increase in effective driving force allows the use of additional injection nozzles 34, which, in turn, reduces the volume in each nozzle 34, which, in turn, reduces the duration of the injection time, etc. Finally, the geometry of the nozzle is determined by the desired diameter of the drug stream, the tensile strength / deformation of the construction materials, and the practical limitations of manufacturing a very small orifice at a cost of effective economy of scale. Although a goal of achieving a portable, compact, lightweight drug delivery device 20, 20a and 20b with respect to the nozzle geometry is "the smaller the better", there are practical limits to construct such nozzles 34. In the Known and conventional needleless drug injectors, these known devices have a relatively large orifice (approximately 0.15 mm-0.20 mm) because these are practical limits of high volume injection molding in suitable thermoplastics (i.e., smaller core pins) that this diameter are not practical at the high pressures and high shear stress required by injection molding in high volume production). As indicated for the drug delivery device 20, 20a and 20b according to the present invention, the drug delivery device 20, 20a and 20b uses nozzles 34 in the size of 50 microns and at a significantly higher operating pressure than that found with conventional known needleless jet injectors, such as those described above. Accordingly, the drug delivery device 20,
20a and 20b in accordance with the present invention takes advantage of materials having high tensile strength and bursting properties for the components of the drug delivery device 20, 20a and 20b. Such materials include ceramics, various metals, metal alloys, high strength engineering thermoplastics (such as PEEK ™, Torlon ™, Ultem ™, etc.), and others. Therefore, the present invention is also directed to the use of the most effective combination in terms of costs of said materials and to minimize the counting of parts, that is, to minimize the number of components and parts required. Since the material used will need to withstand an injection pressure given in excess of 562.4 kg / cm2 immediately at the tip of the nozzle, it is desirable to use discrete nozzles 34 made of metal, metal alloy or ceramic (e.g., alumina or zirconia) and assembling the housing 24 (Figures 1-7B) or supply tube 25 (Figure 8), for example, by bonding or ultrasonic welding. All these materials can be formed by injection molding, although the orifice of the final nozzle would be formed secondarily using laser drilling, ultrasonic drilling, wire EDM machining, or the like. Although not currently believed to be practical, developments in micro-injection molding can make the molding of fully finished integral injection nozzles fully feasible and more cost-effective than current approaches involving secondary finishing operations. However, injection molding in high strength materials coupled with laser drilling to produce accurate, repeatable injection nozzles 34 would satisfy the engineering and cost requirements associated with the present invention. In another example in accordance with the present invention, Figures 1-4 illustrate several views of the drug delivery device 20 that can be used to accelerate a multiplicity of small drug volumes 40 at a rate suitable for delivery in tissue, example, through the skin as part of a transdermal drug delivery procedure. Using this example to illustrate the function of the drug delivery device 20 under the assumption that the design of the drug delivery device 20 will require a total of thirty (30) injection nozzles 34 with each nozzle 34 having a diameter of 40 microns and a calculated drug volume of 3.3 μl per drug reservoir 38, or a total drug volume of 30 x 3.3 = 100 μl. In addition, given a required speed of 200 m / s to supply the drug 40, the force required for each injection nozzle 34 can be calculated from the Hagen-Poiseuilie equation which gives a value of approximately 4.54 kg per injection nozzle 34. Given thirty (30) injection nozzles 34, the total required force is 30 x 4.54 = 136.2 kg. Assuming that the surface area of the main piston 44 is 6.45 cm2, then 136.2 kg of pressure is needed to achieve the required performance parameters. Again, these performance criteria can be achieved using the miniature compressed gas cylinder 36 (figures 8 and 10) or the pyrotechnic charge 64 (figures 2, 3, 7A and 7B). The advantage of the pyrotechnic charge is that the pressure profile can be controlled throughout the supply cycle, providing variable pressures at different times to optimize the drug supply. Moreover, as can be readily appreciated, there may be a number of suitable energy sources that can be used for the purpose of accelerating the drug 40 at the speeds required to achieve microjet propulsion criteria in accordance with the present invention and the examples provided herein are in no way intended to limit the type of energy source that may be used in the present invention. As best illustrated in the graph depicted in figure 11, an in vitro study for the microjet drug delivery device (20, 20a and 20b) was conducted in accordance with the present invention in order to determine an optimal range for depth of penetration (in cm) versus an optimal range of pressure (in kg / cm2). The diameter of the nozzle 34 was a diameter of approximately 50 microns where the volume of drug 40 supplied was approximately 100 μl. As illustrated clearly in Figure 11, the delivery pressures for the drug delivery device per microjet (20, 20a and 20b) can be easily adjusted to objective and selected tissues. Therefore, the drug delivery device per microjet (20, 20a and 20b) is customized in a manner that ensures that any particular drug can be delivered at a particular depth of penetration into a particular tissue type based on a pressure of particular supply according to the graph of Figure 11. Accordingly, this customizable approach even allows particular layers of tissue to be used as a target for drug delivery. For example, the tissue submucouse layer can be used as an objective exactly according to the algorithm shown in Figure 11. In addition, any number of drug reservoirs 38 and injection nozzles 38 can be used for the present invention (within practical limits). As demonstrated above, these can be any from an individual reservoir 38 and an individual nozzle 34 to as many as fifty (50) or more reservoirs 38 and nozzles 34 respectively. Standard semiconductor processes can easily fabricate injection nozzles 34 similar to the manufacture of nozzles used in jet printing. Therefore, the injection nozzles 34 may be mass produced silicon devices having an orifice diameter of between 3 and 10 microns as an example. The injection nozzles 34 can be manufactured as dense arrangements on a silicon wafer and subsequently cut the desired geometry. The wafer patterns, and therefore the layout geometry, can be fabricated into any desired design. Accordingly, the arrangement of micro nozzles can be made in any desired pattern such as a circular, elliptical, or semi-circular pattern, for example, and with any practical density of injection nozzles 34 that is required. Typically, every effort would be made to reduce the size of the injection nozzles 34 and to maximize the number of injection nozzles 34 that said wafer can give. The micromolding of thermoplastics is an emerging technology that may also be useful for manufacturing the drug delivery device 20, 20a and 20b in accordance with the present invention. The advantages would be significant. Although silicon wafers are flat structures, injection molded plastics are not. Therefore, the injection nozzle arrangement 34 can be configured out of plane, for example, which would provide a tremendous benefit to create an arrangement that is intended to be located with objective convergence. An additional significant advantage is the cost. A disposition of micro nozzles molded in a thermoplastic would cost very little, compared to a silicon device that could easily swing in dollars. Other methods that could be used to construct the micro nozzles 34, include micromachining the holes in place as part of the nozzle plate 30 or nozzle plate 30a having a contoured distal end 31 (annular cup), machining or hole formation in glass, metal, ceramic, plastic or other suitable material and then assembled (eg, press fit) into the contoured distal end 31 (annular cup), etc. Like other important components of the drug delivery device 20, 20a and 20b according to the present invention, the design or manufacture of the micro nozzles 34 is not intended to be limited to a specific embodiment. Therefore, in general, the present invention is directed to a method for making or manufacturing a drug delivery device 20, 20a, and 20b in accordance with the present invention. Accordingly, this method comprises several key steps such as identifying a drug to be delivered (it can be based on any desired treatment or disease status or condition that is the purpose of the treatment). In addition, a volume of the drug to be delivered is also defined. Moreover, the key parameters for the characteristics of the device 20, 20a and 20b are determined. This includes parameters such as the diameter for one or more drug reservoirs 38 and the diameter for one or more injection nozzles 34 that are established in advance. In addition, a tissue model is identified for the type of tissue or disease that is to be treated. For example, the tissue model is any in vitro or in vivo model acceptable for this purpose. Therefore, the tissue model can be based on material, for example, tissue model that is synthetic, natural, mammalian (to include any animal or human tissue), living tissue, preserved tissue, etc.
In addition, other key steps include identifying a penetration depth in the tissue model for drug delivery. This includes targeting any desired or particular layer of the tissue that is considered appropriate for injection of microjet of drug 40. In addition, drug 40 is tested in the tissue model by injecting drug 40 into the tissue model using the device. drug delivery 20, 20a and 20b according to the present invention under variable pressure until the desired depth of penetration or desired tissue layer is achieved. By using the method according to the present invention, an optimum pressure range is identified for the drug delivery device 20, 20a and 20b which achieves the desired penetration depth or tissue layer desired. As outlined above, an optimum pressure range has been identified which is < 140.6 kg / cm2 in the main piston 44 and an optimum pressure range of < has been identified; 562.4 kg / cm2 for the area at the tip of the injection nozzle 34. The method according to the present invention also includes the use of predictive modeling to predict the optimum pressure range required in determining the required injection force (F) . The determination of the injection force (F) is achieved according to the formula: F = 8QμL (R2 / r4); wherein Q = drug flow rate; μ = drug viscosity; L = length of the injection nozzle; R = radius of the drug reservoir; and r = radius of the injection nozzle.
Methods of use For transdermal or dermal delivery, the drug delivery device 20 (Figures 1-4) is in its pre-triggered configuration and loaded with the total volume of drug 40 to be delivered where the delivery device of drug 20 is placed firmly against and perpendicular to any desired site of injection (typically the back of the arm, stomach or thigh) with the skin pierced in a conventional manner. Since the injection nozzles 34 terminate as small protrusions projecting from the outer surface nozzle plate 30, the user is provided with instantaneous tactile feedback for proper placement and alignment of the injection nozzles 34 on the tissue surface of the body of the user in the desired injection site. As best shown in Figure 4, by depressing the activation button 74, the strike pin 70 hits the detonator 68 thereby activating the detonator 68, which in turn causes extremely rapid combustion of the pyrotechnic charge 64. This explosion This control provides the necessary driving force to slidably advance the piston 44 and the fixed push rods 48 through the reservoirs 38 by causing the push rods 48 to eject the drug 40 from the injection nozzles by means of microjet jet propulsion. this example described immediately above is directed to subcutaneous or cutaneous delivery, there are other examples for the drug delivery device 20a and 20b which are used in applications such as intra-ocular delivery (drug delivery device 20a), intra-oral delivery ( drug delivery device 20b), intra-nasal (drug delivery device 20b), intra-aural (delivery device 20b) e drug 20b), and, more broadly, intra-mucosal delivery in general (drug delivery device 20, 20a and 20b). It should also be noted that the "transdermal" supply is intended to cover all forms of supply such as: intradermal, subcutaneous and intramuscular. In another embodiment in accordance with the present invention, the drug delivery device 20a (Figures 5, 6, 7A and 7B) is particularly well suited for ocular use and can deliver any drug 40 necessary for intra-ocular microinjection (especially intra-ocular injections). -scleral or intra-vitreai). Such known drugs for these particular applications include VEGF antagonists, corticosteroids and anti-angiogenic drugs in general. Indications treated by the drug delivery device 20a (Figures 5, 6, 7A and 7B) in accordance with the present invention include, for example, diabetic retinopathy, macular degeneration and other diseases involving neovascularization in the eyes. In this embodiment, the contoured distal end or cup 31 is placed above or on the surface of the eyes 100 with the central open portion of the cup 31 overlapping the cornea. The micro nozzles or injection nozzles 34 are spaced apart and configured around the concentric ring of the contoured distal end 31 such that they are in contact with the sclera. In an embodiment according to the present invention, the injection nozzles 31 are configured in a circular or elliptical pattern. However, the present invention contemplates that the injection nozzles 34 are arranged or configured in any desired configuration or pattern. By depressing the activation button 74, the drug injection stream 40, as shown in Figure 5, penetrates deeply into the eye 100 through the sclera, and into the aqueous humor or vitreous humor or any other layer of desired tissue of the eye portion 100. Preferably, the drug 40 injected under microjet propulsion is directed toward the back of the eye 100 as illustrated herein. As mentioned before, currently, many of the drugs of interest are administered by injecting directly into the eye with a conventional needle and syringe. As can be seen to a large extent, this is a somewhat risky procedure and requires that the injection be administered by a trained ophthalmologist. There are significant risks to the patient associated with these conventional techniques and include retinal detachment, scarring after repeated injections, and even blindness. In addition, the injection itself discourages the patient and requires that the patient be very still during the seconds that the injection itself lasts. In the present invention, injection of the drug 40 into the eye 100 is extremely rapid. For example, given a current velocity of the drug 40 injected under microjet propulsion of 100 m / sec for a drug reservoir 38 having a volume of 20 microliters, the complete injection only requires approximately 10 milliseconds using the drug delivery device. 20a in accordance with the present invention. Assuming that the patient would intentionally move the eye 100 from one side to the other during the injection, and assuming that eye movement occurred at a rate of approximately 1 cm / sec, the eye could only move to approximately 1 / 10th of an eye. millimeter in this period, a distance without consequence when the drug delivery device 20a is used in accordance with the present invention. Consequently, this invention also represents a safer and more convenient means of administering drugs to the eyes 100 for both the physician and the patient. As contemplated by the present invention, the drug delivery device 20a (Figures 5, 6, 7 A and 7B) in accordance with the present invention offers a number of advantages over conventional technology and techniques. For example, injection nozzles 34 can be designed to "direct" the injection stream in specific areas in the eye 100 (e.g., the back of the eye 100). In addition, the penetration depth of the drug 40 can be controlled without relying on the skill of the health care provider. Moreover, the risk of damage to the eyes 100 is minimized with the drug delivery device 20a (Figures 5, 6, 7 A and 7B) in accordance with the present invention by minimizing energy and tearing (trauma). to which the eye 100 is subjected due to the extremely rapid nature of the microjet propellant of the drug in eye tissue 100 (estimated to be as fast as approximately 10 milliseconds for the injection of small doses of drug 40). Even more, the drug delivery device 20a has the ability to modulate the jet injection energy and the geometry of the injection stream as a means to control the delivery depth of the drug in the eye. Also, the design of the geometry of the microboquilla allows the control of the diameter, trajectory, cohesion and focus of the current. In addition, the flexibility in the design of the micro-nozzle arrangement allows the optimization of the drug delivery profile for any given drug, disease or disease site within the eye. In addition, the drug delivery device 20a provides an extremely rapid means of administering drug 40 to the eyes 100 in such a way that the movement of the eyes does not present an element of risk. In addition, many drugs currently under clinical and / or clinical investigation are potent drugs and only require the periodic administration of small doses to the eye 100. The drug delivery device 20a (Figures 5, 6, 7A and 7B) in accordance with the present invention offers a more controlled, repeatable, safe and convenient means of delivering these drugs to the eye 100 on any known devices and techniques available to date.
Another embodiment in accordance with the present invention is an intranasal application depicted in Figure 10. Accordingly, the drug delivery device 20b (Figures 8-10) has particularly useful application in the administration of drugs for the CNS (system central nervous) 40 by injection of microjet to the olfactory bulb of the nose 110 of patient 90. In this embodiment, the drug delivery device 20b (FIGS. 8-10) is used to provide direct injection of drug 40 under microjet propulsion in the submucous space of the nose 110 to the CSF of the olfactory lobe. For this purpose, drug doses 40 of 20 mg or more can be injected extremely rapidly (< 50 milliseconds) into the submucosa space and the injection depth can be precisely controlled such that drug 40 is delivered accurately to this area without any penetration damage to an unwanted place. In another embodiment according to the present invention, the drug delivery device 20b is also used for the intra-oral delivery of drug 40 wherein the drug can be micro-injected into any desired area in the mouth such as intra-mucosa for applications such as tumor treatment, ie, targeted delivery of drug under microjet propulsion intended, for example, to treat a tumor. In yet another embodiment in accordance with the present invention, the drug delivery device 20b is used for the intra-aural delivery of drug 40 such that the drug 40 can be microinjected into any desired portion of the ear or ear canal to treat various diseases and conditions of the ears or those conditions that affect, for example, the ear. In addition, in other embodiments according to the present invention, the drug delivery device 20b is also useful for areas of the body that are difficult to access such as various channels, passages, cavities or hard-to-reach surfaces. The extended supply tube 25 facilitates access to these injection sites for injection of drug 40 under microjet propulsion to these difficult areas. Therefore, as described above, the drug delivery device 20, 20a and 20b according to the present invention has many novel features and advantages. Some of these features and novel advantages are summarized here for convenience such as extremely small injection nozzles (0.05 mm or smaller); multiple injection tanks and injection nozzles that reduce to the minimum each injection volume and injection time which results in customizable, variable pressure injections with less pain; which include high pressure injection to reach deep tissues and lower pressure to target shallower tissues; ability to concentrate the dose of drug to a confined area or expand it over a large surface area; high-volume injections divided into a small volume, discrete injectors (can achieve injection volumes equivalent to or greater than conventional jet injectors in faster delivery times; multiple medical applications (ie, transdermal, intra-ocular, intranasal, intra-oral , etc.), efficient operation to include total energy requirements equivalent to those total energy requirements available with the prior art devices, but with the present invention being much quicker to administer the drug and a much less painful injection for the patient, ability to deliver multiple drugs (ie, different drugs can be housed in different drug reservoirs that is not possible with currently known drug delivery devices), and ability to separate excipients during storage up to the time of delivery. the injection which improves the long-term stability of the drug 40. There is no known or existing technology that provides the advantages given by the present invention, including safety, ease of use, accuracy in both dose and depth of penetration, patient comfort and acceptance thereof. Other advantages associated with the present invention is that it can provide the targeted, targeted delivery of small molecules and similar large molecules to include macromolecules such as large proteins, cells or other biological molecules and drugs. In addition, another advantage is that the drug delivery device per microjet according to the present invention is extremely fast in its drug delivery, ie, delivery of approximately <; 10 msec that results in an almost pain-free injection. The present invention contemplates that a significant reduction in the size of the nozzle orifice will result in reduced pain to the patient. In addition, the present invention allows practical new uses of jet injection technology such as transmucosal delivery. An advantage of the present invention is that a plurality of nozzles can be used, arranged in an arrangement and having space between each adjacent nozzle, which defines a flat two-dimensional structure that can be laid flat on the skin and, therefore, ensures perpendicularity. Moreover, the present invention provides true delivery of needleless drugs irrespective of the size of the drug molecules involved and provides true needleless drug delivery with minimal tissue trauma and which are suitable for delivering drugs to sensitive body areas such as eyes, nasal passages, mouth, etc. In addition, the drug delivery device 20, 20a and 20b are simple and efficient in design and construction, low cost and easy to manufacture. Accordingly, the drug delivery device per microjet according to the present invention has an appropriate design that is extremely suitable for a disposable disposable device by the patient, if desired. While the above specification comprises preferred embodiments of the invention, it is understood that variations and modifications can be made here, in accordance with the principles of the invention described, without departing from the scope of the invention. Although preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes and substitutions will occur to one skilled in the art without departing from the invention. Accordingly, it is intended that the invention be limited only by the spirit and scope of the appended claims.
Claims (16)
1. - A method for making a drug delivery device by jet injection, wherein the drug delivery device has at least one drug reservoir and at least one injection nozzle, the method comprising the steps of: identifying a drug to be delivered; identify a volume of the drug to be delivered; establishing a reservoir diameter for at least one drug reservoir; establishing a nozzle diameter for at least one injection nozzle; identify a tissue model to deliver the drug; identify a penetration depth in the tissue model for drug delivery; and injecting the drug into the tissue model under variable pressure until the desired depth of penetration is achieved.
2. The method according to claim 1, further characterized in that it comprises identifying an optimal pressure range for the drug delivery device that achieves the desired depth of penetration.
3. The method according to claim 2, further characterized in that it comprises identifying an optimum pressure range of about 56.24 to about 140.6 kg / cm2.
4. - The method according to claim 2;. further characterized in that it comprises identifying an optimum pressure range of about 281.2 to about 1757.5 kg / cm2 at a tip of at least one injection nozzle.
5. The method according to claim 2, further characterized by comprising using one or more materials for components of the drug delivery device selected from the group comprising: ceramics, metals, metal alloys and thermoplastics.
6. The method according to claim 5, further characterized in that it comprises making a hole in at least one injection nozzle by drilling.
7. The method according to claim 6, further characterized in that it comprises making a hole in at least one injection nozzle by laser drilling.
8. The method according to claim 6, further characterized in that it comprises making a hole in at least one injection nozzle by ultrasonic drilling.
9. The method according to claim 6, further characterized in that it comprises making a hole in at least one injection nozzle by wire machining.
10. The method according to claim 6, further characterized in that it comprises making a hole in at least one injection nozzle by molding or forming.
11. The method according to claim 2, further characterized in that it comprises predicting the optimum pressure range required in determining the required injection force (F) in accordance with the formula: F = 8QμL (R2 / r4); wherein Q = drug flow rate; μ = drug viscosity; L = length of the injection nozzle; R = radius of the drug reservoir; and r = radius of the injection nozzle.
12. The method according to claim 2, further characterized in that it comprises the use of a tissue model that is in vitro.
13. The method according to claim 2, further characterized in that it comprises the use of a tissue model that is in vivo.
14. The method according to claim 4, further characterized in that it comprises driving the drug through a tip of at least one nozzle at a pressure ranging from about 562.4 kg / cm2 to about 843.6 kg / cm2.
15. The method according to claim 13, further characterized in that it comprises driving the drug through a tip of at least one nozzle at a pressure that varies to about 703 kg / cm2.
16. The method according to claim 1, further characterized in that it comprises driving the drug through at least one nozzle within a time ranging from about 10 msec to about 200 msec when activating the power source.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US11200971 | 2005-08-10 |
Publications (1)
Publication Number | Publication Date |
---|---|
MXPA06009041A true MXPA06009041A (en) | 2008-09-02 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU2006203194B2 (en) | Needle-free jet injection drug delivery device | |
KR101267294B1 (en) | Needle-free jet injection drug delivery device | |
KR101291519B1 (en) | Method for making a needle-free jet injection drug delivery device | |
KR101341357B1 (en) | Method for delivering drugs to tissue under microjet propulsion | |
KR101280841B1 (en) | Drug delivery device for buccal and aural applications and other areas of the body difficult to access | |
MXPA06009041A (en) | Method for making a needle-free jet injection drug delivery device | |
MXPA06009039A (en) | Method for delivering drugs to tissue under microjet propulsion | |
MXPA06009040A (en) | Drug delivery device for buccal and aural applications and other areas of the body difficult to access |