JP2006514100A - 徐放性l−アルギニン製剤並びに製造方法および使用方法 - Google Patents
徐放性l−アルギニン製剤並びに製造方法および使用方法 Download PDFInfo
- Publication number
- JP2006514100A JP2006514100A JP2005501690A JP2005501690A JP2006514100A JP 2006514100 A JP2006514100 A JP 2006514100A JP 2005501690 A JP2005501690 A JP 2005501690A JP 2005501690 A JP2005501690 A JP 2005501690A JP 2006514100 A JP2006514100 A JP 2006514100A
- Authority
- JP
- Japan
- Prior art keywords
- arginine
- weight
- subject
- silicon dioxide
- sustained release
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 title claims abstract description 304
- 229930064664 L-arginine Natural products 0.000 title claims abstract description 290
- 235000014852 L-arginine Nutrition 0.000 title claims abstract description 290
- 238000000034 method Methods 0.000 title claims abstract description 220
- 238000013268 sustained release Methods 0.000 title claims description 143
- 239000012730 sustained-release form Substances 0.000 title claims description 143
- 238000004519 manufacturing process Methods 0.000 title claims description 35
- 238000002360 preparation method Methods 0.000 title abstract description 19
- 239000000203 mixture Substances 0.000 claims abstract description 259
- 238000009472 formulation Methods 0.000 claims abstract description 205
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 claims abstract description 106
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 claims abstract description 104
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 claims description 132
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 94
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 82
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 81
- RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 claims description 61
- 229960002855 simvastatin Drugs 0.000 claims description 61
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 claims description 61
- 239000008187 granular material Substances 0.000 claims description 60
- 235000013305 food Nutrition 0.000 claims description 51
- 239000003795 chemical substances by application Substances 0.000 claims description 47
- 235000012000 cholesterol Nutrition 0.000 claims description 42
- 230000001965 increasing effect Effects 0.000 claims description 42
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 42
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 42
- 235000019359 magnesium stearate Nutrition 0.000 claims description 41
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 38
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 38
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 38
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 38
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 36
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 32
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 32
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 32
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 32
- 208000019553 vascular disease Diseases 0.000 claims description 32
- 229940075614 colloidal silicon dioxide Drugs 0.000 claims description 31
- 238000002156 mixing Methods 0.000 claims description 29
- 230000002829 reductive effect Effects 0.000 claims description 29
- YDGMGEXADBMOMJ-LURJTMIESA-N N(g)-dimethylarginine Chemical compound CN(C)C(\N)=N\CCC[C@H](N)C(O)=O YDGMGEXADBMOMJ-LURJTMIESA-N 0.000 claims description 28
- 239000003405 delayed action preparation Substances 0.000 claims description 27
- KWTQSFXGGICVPE-WCCKRBBISA-N Arginine hydrochloride Chemical compound Cl.OC(=O)[C@@H](N)CCCN=C(N)N KWTQSFXGGICVPE-WCCKRBBISA-N 0.000 claims description 25
- 150000003839 salts Chemical class 0.000 claims description 25
- 239000000377 silicon dioxide Substances 0.000 claims description 25
- 235000012239 silicon dioxide Nutrition 0.000 claims description 25
- 239000011230 binding agent Substances 0.000 claims description 24
- 108010074051 C-Reactive Protein Proteins 0.000 claims description 23
- 102100032752 C-reactive protein Human genes 0.000 claims description 23
- 230000024883 vasodilation Effects 0.000 claims description 23
- 238000011282 treatment Methods 0.000 claims description 19
- YDGMGEXADBMOMJ-UHFFFAOYSA-N asymmetrical dimethylarginine Natural products CN(C)C(N)=NCCCC(N)C(O)=O YDGMGEXADBMOMJ-UHFFFAOYSA-N 0.000 claims description 17
- 230000008753 endothelial function Effects 0.000 claims description 14
- 108010010234 HDL Lipoproteins Proteins 0.000 claims description 13
- 102000015779 HDL Lipoproteins Human genes 0.000 claims description 13
- 230000007935 neutral effect Effects 0.000 claims description 13
- 238000008214 LDL Cholesterol Methods 0.000 claims description 11
- 108010007622 LDL Lipoproteins Proteins 0.000 claims description 11
- 102000007330 LDL Lipoproteins Human genes 0.000 claims description 11
- 238000001035 drying Methods 0.000 claims description 10
- 208000024827 Alzheimer disease Diseases 0.000 claims description 9
- 206010059245 Angiopathy Diseases 0.000 claims description 8
- 201000001320 Atherosclerosis Diseases 0.000 claims description 8
- 206010022562 Intermittent claudication Diseases 0.000 claims description 8
- 239000003979 granulating agent Substances 0.000 claims description 8
- 230000002401 inhibitory effect Effects 0.000 claims description 8
- 208000021156 intermittent vascular claudication Diseases 0.000 claims description 8
- 206010048554 Endothelial dysfunction Diseases 0.000 claims description 7
- 230000008694 endothelial dysfunction Effects 0.000 claims description 7
- 230000002265 prevention Effects 0.000 claims description 6
- 238000001238 wet grinding Methods 0.000 claims description 4
- 238000009837 dry grinding Methods 0.000 claims description 3
- 125000002059 L-arginyl group Chemical group O=C([*])[C@](N([H])[H])([H])C([H])([H])C([H])([H])C([H])([H])N([H])C(=N[H])N([H])[H] 0.000 claims description 2
- 238000007580 dry-mixing Methods 0.000 claims description 2
- 229940057948 magnesium stearate Drugs 0.000 claims description 2
- 230000003247 decreasing effect Effects 0.000 claims 2
- 108010022197 lipoprotein cholesterol Proteins 0.000 claims 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 64
- 208000035475 disorder Diseases 0.000 abstract description 36
- 208000024172 Cardiovascular disease Diseases 0.000 abstract description 23
- 208000026106 cerebrovascular disease Diseases 0.000 abstract description 16
- 239000000556 agonist Substances 0.000 abstract description 7
- 239000002243 precursor Substances 0.000 abstract description 5
- 102000008052 Nitric Oxide Synthase Type III Human genes 0.000 abstract 2
- 108010075520 Nitric Oxide Synthase Type III Proteins 0.000 abstract 2
- 239000003826 tablet Substances 0.000 description 63
- 239000003814 drug Substances 0.000 description 53
- 229940079593 drug Drugs 0.000 description 49
- 230000000694 effects Effects 0.000 description 43
- 201000010099 disease Diseases 0.000 description 28
- 238000005469 granulation Methods 0.000 description 26
- 230000003179 granulation Effects 0.000 description 26
- 102000008299 Nitric Oxide Synthase Human genes 0.000 description 25
- 108010021487 Nitric Oxide Synthase Proteins 0.000 description 25
- 210000004027 cell Anatomy 0.000 description 24
- 150000001875 compounds Chemical class 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- 238000007906 compression Methods 0.000 description 18
- 230000006835 compression Effects 0.000 description 18
- 235000002639 sodium chloride Nutrition 0.000 description 18
- 239000000126 substance Substances 0.000 description 17
- 229960003589 arginine hydrochloride Drugs 0.000 description 16
- 230000001419 dependent effect Effects 0.000 description 16
- 210000002889 endothelial cell Anatomy 0.000 description 15
- 210000003038 endothelium Anatomy 0.000 description 14
- 230000008569 process Effects 0.000 description 14
- 239000013543 active substance Substances 0.000 description 13
- 239000002775 capsule Substances 0.000 description 13
- 239000004475 Arginine Substances 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 229960003121 arginine Drugs 0.000 description 12
- 239000000945 filler Substances 0.000 description 12
- -1 for example Proteins 0.000 description 12
- 239000004615 ingredient Substances 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 11
- 230000006870 function Effects 0.000 description 11
- 239000003112 inhibitor Substances 0.000 description 11
- 239000000314 lubricant Substances 0.000 description 11
- 229940096701 plain lipid modifying drug hmg coa reductase inhibitors Drugs 0.000 description 11
- 230000004044 response Effects 0.000 description 11
- 208000024891 symptom Diseases 0.000 description 11
- 210000001519 tissue Anatomy 0.000 description 11
- 102000004286 Hydroxymethylglutaryl CoA Reductases Human genes 0.000 description 10
- 108090000895 Hydroxymethylglutaryl CoA Reductases Proteins 0.000 description 10
- 208000018262 Peripheral vascular disease Diseases 0.000 description 10
- 108090000623 proteins and genes Proteins 0.000 description 10
- 102000004190 Enzymes Human genes 0.000 description 9
- 108090000790 Enzymes Proteins 0.000 description 9
- 102100022397 Nitric oxide synthase, brain Human genes 0.000 description 9
- 101710111444 Nitric oxide synthase, brain Proteins 0.000 description 9
- 101710090055 Nitric oxide synthase, endothelial Proteins 0.000 description 9
- 238000011260 co-administration Methods 0.000 description 9
- 229940088598 enzyme Drugs 0.000 description 9
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 9
- 229920000609 methyl cellulose Polymers 0.000 description 9
- 239000001923 methylcellulose Substances 0.000 description 9
- 235000010981 methylcellulose Nutrition 0.000 description 9
- 239000002245 particle Substances 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 241000699670 Mus sp. Species 0.000 description 8
- 238000000576 coating method Methods 0.000 description 8
- 238000004090 dissolution Methods 0.000 description 8
- 235000018102 proteins Nutrition 0.000 description 8
- 102000004169 proteins and genes Human genes 0.000 description 8
- 239000000523 sample Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 239000012086 standard solution Substances 0.000 description 8
- 206010061216 Infarction Diseases 0.000 description 7
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 239000011248 coating agent Substances 0.000 description 7
- 230000002526 effect on cardiovascular system Effects 0.000 description 7
- 230000007574 infarction Effects 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 239000005541 ACE inhibitor Substances 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 229920003096 Methocel™ K100M Polymers 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 6
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 6
- 235000009697 arginine Nutrition 0.000 description 6
- 210000004204 blood vessel Anatomy 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 238000013329 compounding Methods 0.000 description 6
- 239000012738 dissolution medium Substances 0.000 description 6
- 239000006167 equilibration buffer Substances 0.000 description 6
- 239000012530 fluid Substances 0.000 description 6
- 238000000227 grinding Methods 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 238000005259 measurement Methods 0.000 description 6
- 230000001404 mediated effect Effects 0.000 description 6
- 239000002609 medium Substances 0.000 description 6
- 239000002207 metabolite Substances 0.000 description 6
- 229940069328 povidone Drugs 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 230000001225 therapeutic effect Effects 0.000 description 6
- ZOOGRGPOEVQQDX-UUOKFMHZSA-N 3',5'-cyclic GMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-UUOKFMHZSA-N 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 5
- 108010078321 Guanylate Cyclase Proteins 0.000 description 5
- 102000014469 Guanylate cyclase Human genes 0.000 description 5
- 241000282412 Homo Species 0.000 description 5
- 206010021143 Hypoxia Diseases 0.000 description 5
- RHGKLRLOHDJJDR-BYPYZUCNSA-N L-citrulline Chemical compound NC(=O)NCCC[C@H]([NH3+])C([O-])=O RHGKLRLOHDJJDR-BYPYZUCNSA-N 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- 230000009471 action Effects 0.000 description 5
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 5
- 210000004556 brain Anatomy 0.000 description 5
- 239000011575 calcium Substances 0.000 description 5
- ZOOGRGPOEVQQDX-UHFFFAOYSA-N cyclic GMP Natural products O1C2COP(O)(=O)OC2C(O)C1N1C=NC2=C1NC(N)=NC2=O ZOOGRGPOEVQQDX-UHFFFAOYSA-N 0.000 description 5
- 239000003085 diluting agent Substances 0.000 description 5
- 239000002552 dosage form Substances 0.000 description 5
- 239000007897 gelcap Substances 0.000 description 5
- 230000007954 hypoxia Effects 0.000 description 5
- 238000000338 in vitro Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000011159 matrix material Substances 0.000 description 5
- 239000008188 pellet Substances 0.000 description 5
- 239000008194 pharmaceutical composition Substances 0.000 description 5
- 239000000546 pharmaceutical excipient Substances 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 239000012488 sample solution Substances 0.000 description 5
- 235000000346 sugar Nutrition 0.000 description 5
- 230000002195 synergetic effect Effects 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 4
- 206010003210 Arteriosclerosis Diseases 0.000 description 4
- 102000004127 Cytokines Human genes 0.000 description 4
- 108090000695 Cytokines Proteins 0.000 description 4
- 108010016626 Dipeptides Proteins 0.000 description 4
- 229920003161 Eudragit® RS 30 D Polymers 0.000 description 4
- 108010010803 Gelatin Proteins 0.000 description 4
- 206010020772 Hypertension Diseases 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 239000007983 Tris buffer Substances 0.000 description 4
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 230000004888 barrier function Effects 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 238000004113 cell culture Methods 0.000 description 4
- 235000010980 cellulose Nutrition 0.000 description 4
- 229920002678 cellulose Polymers 0.000 description 4
- 230000002490 cerebral effect Effects 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 208000029078 coronary artery disease Diseases 0.000 description 4
- 239000008367 deionised water Substances 0.000 description 4
- 229910021641 deionized water Inorganic materials 0.000 description 4
- 239000004815 dispersion polymer Substances 0.000 description 4
- 238000007908 dry granulation Methods 0.000 description 4
- 230000003511 endothelial effect Effects 0.000 description 4
- 239000000066 endothelium dependent relaxing factor Substances 0.000 description 4
- 239000008273 gelatin Substances 0.000 description 4
- 229920000159 gelatin Polymers 0.000 description 4
- 229940014259 gelatin Drugs 0.000 description 4
- 235000019322 gelatine Nutrition 0.000 description 4
- 235000011852 gelatine desserts Nutrition 0.000 description 4
- 210000002216 heart Anatomy 0.000 description 4
- 230000001976 improved effect Effects 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 230000001939 inductive effect Effects 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 230000000302 ischemic effect Effects 0.000 description 4
- 208000017169 kidney disease Diseases 0.000 description 4
- 210000002540 macrophage Anatomy 0.000 description 4
- 150000007522 mineralic acids Chemical class 0.000 description 4
- 208000010125 myocardial infarction Diseases 0.000 description 4
- 231100000252 nontoxic Toxicity 0.000 description 4
- 230000003000 nontoxic effect Effects 0.000 description 4
- 150000007524 organic acids Chemical class 0.000 description 4
- 235000005985 organic acids Nutrition 0.000 description 4
- 230000035699 permeability Effects 0.000 description 4
- 208000002815 pulmonary hypertension Diseases 0.000 description 4
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 239000007921 spray Substances 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 229940124597 therapeutic agent Drugs 0.000 description 4
- 231100000331 toxic Toxicity 0.000 description 4
- 230000002588 toxic effect Effects 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 4
- 230000003827 upregulation Effects 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 3
- 102100030988 Angiotensin-converting enzyme Human genes 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
- 102000000584 Calmodulin Human genes 0.000 description 3
- 108010041952 Calmodulin Proteins 0.000 description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
- 206010019280 Heart failures Diseases 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- 229920003091 Methocel™ Polymers 0.000 description 3
- 108010029485 Protein Isoforms Proteins 0.000 description 3
- 102000001708 Protein Isoforms Human genes 0.000 description 3
- 229940123934 Reductase inhibitor Drugs 0.000 description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- 208000007536 Thrombosis Diseases 0.000 description 3
- XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 210000002403 aortic endothelial cell Anatomy 0.000 description 3
- 150000001483 arginine derivatives Chemical class 0.000 description 3
- 208000011775 arteriosclerosis disease Diseases 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- 230000033228 biological regulation Effects 0.000 description 3
- 230000017531 blood circulation Effects 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 229910052791 calcium Inorganic materials 0.000 description 3
- 239000001506 calcium phosphate Substances 0.000 description 3
- 239000001768 carboxy methyl cellulose Substances 0.000 description 3
- 239000001913 cellulose Substances 0.000 description 3
- 229960002173 citrulline Drugs 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
- 230000001934 delay Effects 0.000 description 3
- 239000008121 dextrose Substances 0.000 description 3
- 239000007884 disintegrant Substances 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 239000000796 flavoring agent Substances 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- 230000036541 health Effects 0.000 description 3
- 230000006698 induction Effects 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 210000003734 kidney Anatomy 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 108020004999 messenger RNA Proteins 0.000 description 3
- 238000000465 moulding Methods 0.000 description 3
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 3
- 230000036470 plasma concentration Effects 0.000 description 3
- 230000000069 prophylactic effect Effects 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 229920005989 resin Polymers 0.000 description 3
- 239000011347 resin Substances 0.000 description 3
- 239000002002 slurry Substances 0.000 description 3
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 3
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 3
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 3
- 238000005507 spraying Methods 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 229940032147 starch Drugs 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 150000008163 sugars Chemical class 0.000 description 3
- 239000007939 sustained release tablet Substances 0.000 description 3
- 239000007916 tablet composition Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 210000005166 vasculature Anatomy 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- 238000005550 wet granulation Methods 0.000 description 3
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 2
- FJLGEFLZQAZZCD-JUFISIKESA-N (3S,5R)-fluvastatin Chemical compound C12=CC=CC=C2N(C(C)C)C(\C=C\[C@H](O)C[C@H](O)CC(O)=O)=C1C1=CC=C(F)C=C1 FJLGEFLZQAZZCD-JUFISIKESA-N 0.000 description 2
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 description 2
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 101800004538 Bradykinin Proteins 0.000 description 2
- 102400000967 Bradykinin Human genes 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 2
- QXZGBUJJYSLZLT-UHFFFAOYSA-N H-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg-OH Natural products NC(N)=NCCCC(N)C(=O)N1CCCC1C(=O)N1C(C(=O)NCC(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CO)C(=O)N2C(CCC2)C(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CCCN=C(N)N)C(O)=O)CCC1 QXZGBUJJYSLZLT-UHFFFAOYSA-N 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 2
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- 208000031226 Hyperlipidaemia Diseases 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 2
- 108010028554 LDL Cholesterol Proteins 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 229920000881 Modified starch Polymers 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 206010063837 Reperfusion injury Diseases 0.000 description 2
- AJLFOPYRIVGYMJ-UHFFFAOYSA-N SJ000287055 Natural products C12C(OC(=O)C(C)CC)CCC=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 AJLFOPYRIVGYMJ-UHFFFAOYSA-N 0.000 description 2
- 102000007637 Soluble Guanylyl Cyclase Human genes 0.000 description 2
- 108010007205 Soluble Guanylyl Cyclase Proteins 0.000 description 2
- 238000000692 Student's t-test Methods 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 2
- 229960004373 acetylcholine Drugs 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 239000000783 alginic acid Substances 0.000 description 2
- 229960001126 alginic acid Drugs 0.000 description 2
- 150000004781 alginic acids Chemical class 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 229940127003 anti-diabetic drug Drugs 0.000 description 2
- 239000003472 antidiabetic agent Substances 0.000 description 2
- 239000002111 antiemetic agent Substances 0.000 description 2
- 239000003429 antifungal agent Substances 0.000 description 2
- 239000002830 appetite depressant Substances 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 229940077388 benzenesulfonate Drugs 0.000 description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 2
- 230000036983 biotransformation Effects 0.000 description 2
- 230000036772 blood pressure Effects 0.000 description 2
- QXZGBUJJYSLZLT-FDISYFBBSA-N bradykinin Chemical compound NC(=N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(=O)NCC(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CO)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)CCC1 QXZGBUJJYSLZLT-FDISYFBBSA-N 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 239000007963 capsule composition Substances 0.000 description 2
- 125000004181 carboxyalkyl group Chemical group 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 229920001429 chelating resin Polymers 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 239000000812 cholinergic antagonist Substances 0.000 description 2
- 230000004087 circulation Effects 0.000 description 2
- 235000015165 citric acid Nutrition 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 238000005056 compaction Methods 0.000 description 2
- 230000002860 competitive effect Effects 0.000 description 2
- 238000013270 controlled release Methods 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 239000003246 corticosteroid Substances 0.000 description 2
- 229960001334 corticosteroids Drugs 0.000 description 2
- 230000003412 degenerative effect Effects 0.000 description 2
- 230000003111 delayed effect Effects 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 235000013399 edible fruits Nutrition 0.000 description 2
- 239000002158 endotoxin Substances 0.000 description 2
- 239000000262 estrogen Substances 0.000 description 2
- 229940011871 estrogen Drugs 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 239000003527 fibrinolytic agent Substances 0.000 description 2
- 235000019634 flavors Nutrition 0.000 description 2
- 238000009477 fluid bed granulation Methods 0.000 description 2
- 238000005243 fluidization Methods 0.000 description 2
- 239000003862 glucocorticoid Substances 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 239000004220 glutamic acid Substances 0.000 description 2
- 235000013402 health food Nutrition 0.000 description 2
- 239000011539 homogenization buffer Substances 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 239000002955 immunomodulating agent Substances 0.000 description 2
- 229940121354 immunomodulator Drugs 0.000 description 2
- 230000002584 immunomodulator Effects 0.000 description 2
- 201000001881 impotence Diseases 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 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 2
- 230000003834 intracellular effect Effects 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 230000000873 masking effect Effects 0.000 description 2
- 125000005395 methacrylic acid group Chemical group 0.000 description 2
- AJLFOPYRIVGYMJ-INTXDZFKSA-N mevastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=CCC[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 AJLFOPYRIVGYMJ-INTXDZFKSA-N 0.000 description 2
- BOZILQFLQYBIIY-UHFFFAOYSA-N mevastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CCC=C21 BOZILQFLQYBIIY-UHFFFAOYSA-N 0.000 description 2
- 238000003801 milling Methods 0.000 description 2
- 210000002464 muscle smooth vascular Anatomy 0.000 description 2
- 210000000653 nervous system Anatomy 0.000 description 2
- 210000002569 neuron Anatomy 0.000 description 2
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 2
- 229910017604 nitric acid Inorganic materials 0.000 description 2
- 235000015097 nutrients Nutrition 0.000 description 2
- 238000005457 optimization Methods 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 230000007170 pathology Effects 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000000750 progressive effect Effects 0.000 description 2
- 235000013930 proline Nutrition 0.000 description 2
- 150000003148 prolines Chemical class 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 239000011535 reaction buffer Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 238000009490 roller compaction Methods 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 235000010413 sodium alginate Nutrition 0.000 description 2
- 239000000661 sodium alginate Substances 0.000 description 2
- 229940005550 sodium alginate Drugs 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 239000000021 stimulant Substances 0.000 description 2
- 230000004936 stimulating effect Effects 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 238000012353 t test Methods 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 231100001274 therapeutic index Toxicity 0.000 description 2
- 239000005495 thyroid hormone Substances 0.000 description 2
- 229940036555 thyroid hormone Drugs 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 238000013518 transcription Methods 0.000 description 2
- 230000035897 transcription Effects 0.000 description 2
- 230000001052 transient effect Effects 0.000 description 2
- 230000014616 translation Effects 0.000 description 2
- 150000003626 triacylglycerols Chemical class 0.000 description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 2
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- 210000004509 vascular smooth muscle cell Anatomy 0.000 description 2
- 230000006442 vascular tone Effects 0.000 description 2
- 229940124549 vasodilator Drugs 0.000 description 2
- 239000003071 vasodilator agent Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- UIWFNAGAOVYCNU-LBFNQQAFSA-N (2s)-2-amino-5-(diaminomethylideneamino)pentanoic acid;(2s,3s)-2-amino-3-methylpentanoic acid Chemical compound CC[C@H](C)[C@H](N)C(O)=O.OC(=O)[C@@H](N)CCCNC(N)=N UIWFNAGAOVYCNU-LBFNQQAFSA-N 0.000 description 1
- VMDCTAGTCGYQDX-WCCKRBBISA-N (2s)-2-amino-5-(diaminomethylideneamino)pentanoic acid;pyridine-3-carboxylic acid Chemical compound [O-]C(=O)C1=CC=CN=C1.NC(N)=NCCC[C@H]([NH3+])C(O)=O VMDCTAGTCGYQDX-WCCKRBBISA-N 0.000 description 1
- SUUWYOYAXFUOLX-ZBRNBAAYSA-N (2s)-2-aminobutanedioic acid;(2s)-2-amino-5-(diaminomethylideneamino)pentanoic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O.OC(=O)[C@@H](N)CCCN=C(N)N SUUWYOYAXFUOLX-ZBRNBAAYSA-N 0.000 description 1
- BIDNLKIUORFRQP-XYGFDPSESA-N (2s,4s)-4-cyclohexyl-1-[2-[[(1s)-2-methyl-1-propanoyloxypropoxy]-(4-phenylbutyl)phosphoryl]acetyl]pyrrolidine-2-carboxylic acid Chemical compound C([P@@](=O)(O[C@H](OC(=O)CC)C(C)C)CC(=O)N1[C@@H](C[C@H](C1)C1CCCCC1)C(O)=O)CCCC1=CC=CC=C1 BIDNLKIUORFRQP-XYGFDPSESA-N 0.000 description 1
- CABVTRNMFUVUDM-VRHQGPGLSA-N (3S)-3-hydroxy-3-methylglutaryl-CoA Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)C[C@@](O)(CC(O)=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 CABVTRNMFUVUDM-VRHQGPGLSA-N 0.000 description 1
- CUKWUWBLQQDQAC-VEQWQPCFSA-N (3s)-3-amino-4-[[(2s)-1-[[(2s)-1-[[(2s)-1-[[(2s,3s)-1-[[(2s)-1-[(2s)-2-[[(1s)-1-carboxyethyl]carbamoyl]pyrrolidin-1-yl]-3-(1h-imidazol-5-yl)-1-oxopropan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-3-methyl-1-ox Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C)C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C1=CC=C(O)C=C1 CUKWUWBLQQDQAC-VEQWQPCFSA-N 0.000 description 1
- VDSBXXDKCUBMQC-HNGSOEQISA-N (4r,6s)-6-[(e)-2-[2-(4-fluoro-3-methylphenyl)-4,4,6,6-tetramethylcyclohexen-1-yl]ethenyl]-4-hydroxyoxan-2-one Chemical compound C1=C(F)C(C)=CC(C=2CC(C)(C)CC(C)(C)C=2\C=C\[C@H]2OC(=O)C[C@H](O)C2)=C1 VDSBXXDKCUBMQC-HNGSOEQISA-N 0.000 description 1
- VIMMECPCYZXUCI-MIMFYIINSA-N (4s,6r)-6-[(1e)-4,4-bis(4-fluorophenyl)-3-(1-methyltetrazol-5-yl)buta-1,3-dienyl]-4-hydroxyoxan-2-one Chemical compound CN1N=NN=C1C(\C=C\[C@@H]1OC(=O)C[C@@H](O)C1)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 VIMMECPCYZXUCI-MIMFYIINSA-N 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- KWTQSFXGGICVPE-UHFFFAOYSA-N 2-amino-5-(diaminomethylideneamino)pentanoic acid;hydron;chloride Chemical compound Cl.OC(=O)C(N)CCCN=C(N)N KWTQSFXGGICVPE-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 108010062271 Acute-Phase Proteins Proteins 0.000 description 1
- 102000011767 Acute-Phase Proteins Human genes 0.000 description 1
- 229930024421 Adenine Natural products 0.000 description 1
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 102400000344 Angiotensin-1 Human genes 0.000 description 1
- 101800000734 Angiotensin-1 Proteins 0.000 description 1
- 102400000345 Angiotensin-2 Human genes 0.000 description 1
- 101800000733 Angiotensin-2 Proteins 0.000 description 1
- 101710129690 Angiotensin-converting enzyme inhibitor Proteins 0.000 description 1
- 200000000007 Arterial disease Diseases 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 description 1
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 description 1
- 229920003084 Avicel® PH-102 Polymers 0.000 description 1
- XPCFTKFZXHTYIP-PMACEKPBSA-N Benazepril Chemical compound C([C@@H](C(=O)OCC)N[C@@H]1C(N(CC(O)=O)C2=CC=CC=C2CC1)=O)CC1=CC=CC=C1 XPCFTKFZXHTYIP-PMACEKPBSA-N 0.000 description 1
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 229940078581 Bone resorption inhibitor Drugs 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 101710086378 Bradykinin-potentiating and C-type natriuretic peptides Proteins 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 229940122072 Carbonic anhydrase inhibitor Drugs 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- GHOKWGTUZJEAQD-UHFFFAOYSA-N Chick antidermatitis factor Natural products OCC(C)(C)C(O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-UHFFFAOYSA-N 0.000 description 1
- 102000003914 Cholinesterases Human genes 0.000 description 1
- 108090000322 Cholinesterases Proteins 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- VGMFHMLQOYWYHN-UHFFFAOYSA-N Compactin Natural products OCC1OC(OC2C(O)C(O)C(CO)OC2Oc3cc(O)c4C(=O)C(=COc4c3)c5ccc(O)c(O)c5)C(O)C(O)C1O VGMFHMLQOYWYHN-UHFFFAOYSA-N 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- 206010011985 Decubitus ulcer Diseases 0.000 description 1
- 101000783577 Dendroaspis angusticeps Thrombostatin Proteins 0.000 description 1
- 101000783578 Dendroaspis jamesoni kaimosae Dendroaspin Proteins 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 108010061435 Enalapril Proteins 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 208000030644 Esophageal Motility disease Diseases 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- 208000012895 Gastric disease Diseases 0.000 description 1
- 241000237858 Gastropoda Species 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 102000006771 Gonadotropins Human genes 0.000 description 1
- 108010086677 Gonadotropins Proteins 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 108010023302 HDL Cholesterol Proteins 0.000 description 1
- LJIZUXQINHXGAO-ITWZMISCSA-N HR 780 Chemical compound C(\[C@H]1OC(=O)C[C@H](O)C1)=C/C=1C(C(C)C)=NC(C=2C=CC=CC=2)=CC=1C1=CC=C(F)C=C1 LJIZUXQINHXGAO-ITWZMISCSA-N 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- SQUHHTBVTRBESD-UHFFFAOYSA-N Hexa-Ac-myo-Inositol Natural products CC(=O)OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O SQUHHTBVTRBESD-UHFFFAOYSA-N 0.000 description 1
- 206010020365 Homocystinuria Diseases 0.000 description 1
- 208000035150 Hypercholesterolemia Diseases 0.000 description 1
- 206010020880 Hypertrophy Diseases 0.000 description 1
- 238000012369 In process control Methods 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 208000032382 Ischaemic stroke Diseases 0.000 description 1
- 235000019766 L-Lysine Nutrition 0.000 description 1
- 150000008535 L-arginines Chemical class 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229920002774 Maltodextrin Polymers 0.000 description 1
- 239000005913 Maltodextrin Substances 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 101150031207 NOS3 gene Proteins 0.000 description 1
- RHGKLRLOHDJJDR-UHFFFAOYSA-N Ndelta-carbamoyl-DL-ornithine Natural products OC(=O)C(N)CCCNC(N)=O RHGKLRLOHDJJDR-UHFFFAOYSA-N 0.000 description 1
- 240000002853 Nelumbo nucifera Species 0.000 description 1
- 235000006508 Nelumbo nucifera Nutrition 0.000 description 1
- 235000006510 Nelumbo pentapetala Nutrition 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- SNIOPGDIGTZGOP-UHFFFAOYSA-N Nitroglycerin Chemical compound [O-][N+](=O)OCC(O[N+]([O-])=O)CO[N+]([O-])=O SNIOPGDIGTZGOP-UHFFFAOYSA-N 0.000 description 1
- 239000000006 Nitroglycerin Substances 0.000 description 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-N Nitrous acid Chemical compound ON=O IOVCWXUNBOPUCH-UHFFFAOYSA-N 0.000 description 1
- 239000004677 Nylon Substances 0.000 description 1
- 208000010191 Osteitis Deformans Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 239000002033 PVDF binder Substances 0.000 description 1
- 208000027868 Paget disease Diseases 0.000 description 1
- 208000031481 Pathologic Constriction Diseases 0.000 description 1
- 108010001014 Plasminogen Activators Proteins 0.000 description 1
- 102000001938 Plasminogen Activators Human genes 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical class 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
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- AUNGANRZJHBGPY-SCRDCRAPSA-N Riboflavin Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-SCRDCRAPSA-N 0.000 description 1
- 208000034189 Sclerosis Diseases 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 108010073771 Soybean Proteins Proteins 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 229930182558 Sterol Natural products 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 108090000190 Thrombin Proteins 0.000 description 1
- AUYYCJSJGJYCDS-LBPRGKRZSA-N Thyrolar Chemical class IC1=CC(C[C@H](N)C(O)=O)=CC(I)=C1OC1=CC=C(O)C(I)=C1 AUYYCJSJGJYCDS-LBPRGKRZSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 1
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 description 1
- 201000004810 Vascular dementia Diseases 0.000 description 1
- 206010047141 Vasodilatation Diseases 0.000 description 1
- 239000005862 Whey Substances 0.000 description 1
- 102000007544 Whey Proteins Human genes 0.000 description 1
- 108010046377 Whey Proteins Proteins 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 229940123769 Xanthine oxidase inhibitor Drugs 0.000 description 1
- 229920002494 Zein Polymers 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- VVGPECAOVDZTLZ-UHFFFAOYSA-N [N]NC(N)=N Chemical compound [N]NC(N)=N VVGPECAOVDZTLZ-UHFFFAOYSA-N 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 230000009692 acute damage Effects 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 229960000643 adenine Drugs 0.000 description 1
- 239000000464 adrenergic agent Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 238000005054 agglomeration Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 239000002170 aldosterone antagonist Substances 0.000 description 1
- 229940083712 aldosterone antagonist Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 229940093740 amino acid and derivative Drugs 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 229940124325 anabolic agent Drugs 0.000 description 1
- 239000003263 anabolic agent Substances 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- ORWYRWWVDCYOMK-HBZPZAIKSA-N angiotensin I Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C1=CC=C(O)C=C1 ORWYRWWVDCYOMK-HBZPZAIKSA-N 0.000 description 1
- 229950006323 angiotensin ii Drugs 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 229940125709 anorectic agent Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 239000000921 anthelmintic agent Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000001466 anti-adreneric effect Effects 0.000 description 1
- 230000002280 anti-androgenic effect Effects 0.000 description 1
- 230000001088 anti-asthma Effects 0.000 description 1
- 230000000879 anti-atherosclerotic effect Effects 0.000 description 1
- 230000003474 anti-emetic effect Effects 0.000 description 1
- 229940046836 anti-estrogen Drugs 0.000 description 1
- 230000001833 anti-estrogenic effect Effects 0.000 description 1
- 230000001567 anti-fibrinolytic effect Effects 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000001384 anti-glaucoma Effects 0.000 description 1
- 230000002924 anti-infective effect Effects 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 230000002553 anti-keratinizing effect Effects 0.000 description 1
- 239000000883 anti-obesity agent Substances 0.000 description 1
- 229940035678 anti-parkinson drug Drugs 0.000 description 1
- 230000003473 anti-pneumocystis Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 230000001826 anti-prostatic effect Effects 0.000 description 1
- 230000000561 anti-psychotic effect Effects 0.000 description 1
- 239000000043 antiallergic agent Substances 0.000 description 1
- 239000000051 antiandrogen Substances 0.000 description 1
- 229940124347 antiarthritic drug Drugs 0.000 description 1
- 239000000924 antiasthmatic agent Substances 0.000 description 1
- 229940124350 antibacterial drug Drugs 0.000 description 1
- 239000003529 anticholesteremic agent Substances 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 229940125683 antiemetic agent Drugs 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 229940082620 antifibrinolytics Drugs 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 229940030225 antihemorrhagics Drugs 0.000 description 1
- 229940124623 antihistamine drug Drugs 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940127088 antihypertensive drug Drugs 0.000 description 1
- 239000003524 antilipemic agent Substances 0.000 description 1
- 239000003430 antimalarial agent Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000003096 antiparasitic agent Substances 0.000 description 1
- 229940127218 antiplatelet drug Drugs 0.000 description 1
- 239000003904 antiprotozoal agent Substances 0.000 description 1
- 239000003908 antipruritic agent Substances 0.000 description 1
- 239000003435 antirheumatic agent Substances 0.000 description 1
- 239000003200 antithyroid agent Substances 0.000 description 1
- 239000003434 antitussive agent Substances 0.000 description 1
- 229940124584 antitussives Drugs 0.000 description 1
- 239000003699 antiulcer agent Substances 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 229960002223 arginine aspartate Drugs 0.000 description 1
- 230000003143 atherosclerotic effect Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 229960005370 atorvastatin Drugs 0.000 description 1
- 210000002199 attachment cell Anatomy 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- 210000000941 bile Anatomy 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 210000002302 brachial artery Anatomy 0.000 description 1
- 230000006931 brain damage Effects 0.000 description 1
- 231100000874 brain damage Toxicity 0.000 description 1
- 208000029028 brain injury Diseases 0.000 description 1
- 229940124630 bronchodilator Drugs 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 239000003710 calcium ionophore Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 229940095672 calcium sulfate Drugs 0.000 description 1
- 235000011132 calcium sulphate Nutrition 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 229960000830 captopril Drugs 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
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 229960001631 carbomer Drugs 0.000 description 1
- 239000003489 carbonate dehydratase inhibitor Substances 0.000 description 1
- 210000004413 cardiac myocyte Anatomy 0.000 description 1
- 239000000496 cardiotonic agent Substances 0.000 description 1
- 239000002327 cardiovascular agent Substances 0.000 description 1
- 229940125692 cardiovascular agent Drugs 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 229920003086 cellulose ether Polymers 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 229960005110 cerivastatin Drugs 0.000 description 1
- SEERZIQQUAZTOL-ANMDKAQQSA-N cerivastatin Chemical compound COCC1=C(C(C)C)N=C(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC(O)=O)=C1C1=CC=C(F)C=C1 SEERZIQQUAZTOL-ANMDKAQQSA-N 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- VDANGULDQQJODZ-UHFFFAOYSA-N chloroprocaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1Cl VDANGULDQQJODZ-UHFFFAOYSA-N 0.000 description 1
- 229960002023 chloroprocaine Drugs 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229940127243 cholinergic drug Drugs 0.000 description 1
- 229940048961 cholinesterase Drugs 0.000 description 1
- 229960005025 cilazapril Drugs 0.000 description 1
- HHHKFGXWKKUNCY-FHWLQOOXSA-N cilazapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H]1C(N2[C@@H](CCCN2CCC1)C(O)=O)=O)CC1=CC=CC=C1 HHHKFGXWKKUNCY-FHWLQOOXSA-N 0.000 description 1
- 235000013477 citrulline Nutrition 0.000 description 1
- 230000019771 cognition Effects 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 229940099112 cornstarch Drugs 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 239000000824 cytostatic agent Substances 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 229950003040 dalvastatin Drugs 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 239000000850 decongestant Substances 0.000 description 1
- 229940124581 decongestants Drugs 0.000 description 1
- 230000007123 defense Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000000280 densification Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 229960002086 dextran Drugs 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 229940043237 diethanolamine Drugs 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 230000000916 dilatatory effect Effects 0.000 description 1
- 230000010339 dilation Effects 0.000 description 1
- 229910001882 dioxygen Inorganic materials 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- 229940052760 dopamine agonists Drugs 0.000 description 1
- 239000003136 dopamine receptor stimulating agent Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 244000078703 ectoparasite Species 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 239000002895 emetic Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 229960000873 enalapril Drugs 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
- 238000005538 encapsulation Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 230000007515 enzymatic degradation Effects 0.000 description 1
- 230000007071 enzymatic hydrolysis Effects 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 238000011067 equilibration Methods 0.000 description 1
- 230000008029 eradication Effects 0.000 description 1
- 239000000328 estrogen antagonist Substances 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 229960004667 ethyl cellulose Drugs 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 1
- 229940012017 ethylenediamine Drugs 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000003172 expectorant agent Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 235000020937 fasting conditions Nutrition 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- VWWQXMAJTJZDQX-UYBVJOGSSA-N flavin adenine dinucleotide Chemical compound C1=NC2=C(N)N=CN=C2N1[C@@H]([C@H](O)[C@@H]1O)O[C@@H]1CO[P@](O)(=O)O[P@@](O)(=O)OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C2=NC(=O)NC(=O)C2=NC2=C1C=C(C)C(C)=C2 VWWQXMAJTJZDQX-UYBVJOGSSA-N 0.000 description 1
- 235000019162 flavin adenine dinucleotide Nutrition 0.000 description 1
- 239000011714 flavin adenine dinucleotide Substances 0.000 description 1
- 229940093632 flavin-adenine dinucleotide Drugs 0.000 description 1
- 229960003765 fluvastatin Drugs 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000011194 food seasoning agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 229960002490 fosinopril Drugs 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 230000005176 gastrointestinal motility Effects 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 125000003976 glyceryl group Chemical group [H]C([*])([H])C(O[H])([H])C(O[H])([H])[H] 0.000 description 1
- FETSQPAGYOVAQU-UHFFFAOYSA-N glyceryl palmitostearate Chemical compound OCC(O)CO.CCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O FETSQPAGYOVAQU-UHFFFAOYSA-N 0.000 description 1
- 229940046813 glyceryl palmitostearate Drugs 0.000 description 1
- 229960003711 glyceryl trinitrate Drugs 0.000 description 1
- 239000002622 gonadotropin Substances 0.000 description 1
- 239000003966 growth inhibitor Substances 0.000 description 1
- 239000002874 hemostatic agent Substances 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 229920001903 high density polyethylene Polymers 0.000 description 1
- 239000004700 high-density polyethylene Substances 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 239000003485 histamine H2 receptor antagonist Substances 0.000 description 1
- 229920001519 homopolymer Polymers 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 230000000887 hydrating effect Effects 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000010514 hydrogenated cottonseed oil Substances 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 230000000260 hypercholesteremic effect Effects 0.000 description 1
- 238000010191 image analysis Methods 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 230000000091 immunopotentiator Effects 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 229940124589 immunosuppressive drug Drugs 0.000 description 1
- 238000010965 in-process control Methods 0.000 description 1
- 230000000415 inactivating effect Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 210000004969 inflammatory cell Anatomy 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 description 1
- 229960000367 inositol Drugs 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 229940045996 isethionic acid Drugs 0.000 description 1
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 239000003410 keratolytic agent Substances 0.000 description 1
- BJHIKXHVCXFQLS-UYFOZJQFSA-N keto-D-fructose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)C(=O)CO BJHIKXHVCXFQLS-UYFOZJQFSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 229920006008 lipopolysaccharide Polymers 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
- 229910052744 lithium Inorganic materials 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 230000033001 locomotion Effects 0.000 description 1
- 230000027928 long-term synaptic potentiation Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229960004844 lovastatin Drugs 0.000 description 1
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 description 1
- QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 229940037627 magnesium lauryl sulfate Drugs 0.000 description 1
- HBNDBUATLJAUQM-UHFFFAOYSA-L magnesium;dodecyl sulfate Chemical compound [Mg+2].CCCCCCCCCCCCOS([O-])(=O)=O.CCCCCCCCCCCCOS([O-])(=O)=O HBNDBUATLJAUQM-UHFFFAOYSA-L 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229940035034 maltodextrin Drugs 0.000 description 1
- 208000027202 mammary Paget disease Diseases 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 229960001855 mannitol Drugs 0.000 description 1
- 238000005360 mashing Methods 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000036997 mental performance Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229950009116 mevastatin Drugs 0.000 description 1
- 239000013586 microbial product Substances 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 230000003228 microsomal effect Effects 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 229940042472 mineral oil Drugs 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 235000013379 molasses Nutrition 0.000 description 1
- 239000007932 molded tablet Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 229940066491 mucolytics Drugs 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 239000002637 mydriatic agent Substances 0.000 description 1
- 230000002911 mydriatic effect Effects 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- 210000000107 myocyte Anatomy 0.000 description 1
- 239000003703 n methyl dextro aspartic acid receptor blocking agent Substances 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 239000000842 neuromuscular blocking agent Substances 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 229920001778 nylon Polymers 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 235000019645 odor Nutrition 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000002895 organic esters Chemical class 0.000 description 1
- 108010071584 oxidized low density lipoprotein Proteins 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- 229940055726 pantothenic acid Drugs 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- 230000032696 parturition Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 238000005453 pelletization Methods 0.000 description 1
- 235000019371 penicillin G benzathine Nutrition 0.000 description 1
- 229960002582 perindopril Drugs 0.000 description 1
- IPVQLZZIHOAWMC-QXKUPLGCSA-N perindopril Chemical compound C1CCC[C@H]2C[C@@H](C(O)=O)N(C(=O)[C@H](C)N[C@@H](CCC)C(=O)OCC)[C@H]21 IPVQLZZIHOAWMC-QXKUPLGCSA-N 0.000 description 1
- 210000001428 peripheral nervous system Anatomy 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- 230000009120 phenotypic response Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229960002797 pitavastatin Drugs 0.000 description 1
- VGYFMXBACGZSIL-MCBHFWOFSA-N pitavastatin Chemical compound OC(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C2CC2)N=C2C=CC=CC2=C1C1=CC=C(F)C=C1 VGYFMXBACGZSIL-MCBHFWOFSA-N 0.000 description 1
- 230000001817 pituitary effect Effects 0.000 description 1
- 229940127126 plasminogen activator Drugs 0.000 description 1
- 239000000106 platelet aggregation inhibitor Substances 0.000 description 1
- 229920003229 poly(methyl methacrylate) Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000004926 polymethyl methacrylate Substances 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 150000004804 polysaccharides Chemical class 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 230000001323 posttranslational effect Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 229940116317 potato starch Drugs 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 229960001495 pravastatin sodium Drugs 0.000 description 1
- VWBQYTRBTXKKOG-IYNICTALSA-M pravastatin sodium Chemical compound [Na+].C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC([O-])=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 VWBQYTRBTXKKOG-IYNICTALSA-M 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 238000002203 pretreatment Methods 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 238000011112 process operation Methods 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 239000000583 progesterone congener Substances 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 201000004240 prostatic hypertrophy Diseases 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 239000011251 protective drug Substances 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 229940001470 psychoactive drug Drugs 0.000 description 1
- 239000004089 psychotropic agent Substances 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 229960001455 quinapril Drugs 0.000 description 1
- JSDRRTOADPPCHY-HSQYWUDLSA-N quinapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CC2=CC=CC=C2C1)C(O)=O)CC1=CC=CC=C1 JSDRRTOADPPCHY-HSQYWUDLSA-N 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 229940121896 radiopharmaceutical Drugs 0.000 description 1
- 239000012217 radiopharmaceutical Substances 0.000 description 1
- 230000002799 radiopharmaceutical effect Effects 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
- 238000011084 recovery Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000008844 regulatory mechanism Effects 0.000 description 1
- 230000004648 relaxation of smooth muscle Effects 0.000 description 1
- 230000033904 relaxation of vascular smooth muscle Effects 0.000 description 1
- 206010038464 renal hypertension Diseases 0.000 description 1
- 230000036454 renin-angiotensin system Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- QEVHRUUCFGRFIF-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C(C5=CC=C(OC)C=C5N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 QEVHRUUCFGRFIF-MDEJGZGSSA-N 0.000 description 1
- 208000037803 restenosis Diseases 0.000 description 1
- 208000004124 rheumatic heart disease Diseases 0.000 description 1
- 229940100486 rice starch Drugs 0.000 description 1
- 229960000672 rosuvastatin Drugs 0.000 description 1
- BPRHUIZQVSMCRT-VEUZHWNKSA-N rosuvastatin Chemical compound CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC(O)=O BPRHUIZQVSMCRT-VEUZHWNKSA-N 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 201000004409 schistosomiasis Diseases 0.000 description 1
- 239000003229 sclerosing agent Substances 0.000 description 1
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 1
- 230000000580 secretagogue effect Effects 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 229940125723 sedative agent Drugs 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 230000001953 sensory effect Effects 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 238000010008 shearing Methods 0.000 description 1
- 239000002893 slag Substances 0.000 description 1
- 238000009491 slugging Methods 0.000 description 1
- 230000000391 smoking effect Effects 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- BBMHARZCALWXSL-UHFFFAOYSA-M sodium dihydrogenphosphate monohydrate Chemical compound O.[Na+].OP(O)([O-])=O BBMHARZCALWXSL-UHFFFAOYSA-M 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- FPQYXAFKHLSWTI-UHFFFAOYSA-M sodium;pentane-1-sulfonate;hydrate Chemical compound O.[Na+].CCCCCS([O-])(=O)=O FPQYXAFKHLSWTI-UHFFFAOYSA-M 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 229940001941 soy protein Drugs 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000036262 stenosis Effects 0.000 description 1
- 208000037804 stenosis Diseases 0.000 description 1
- 150000003432 sterols Chemical class 0.000 description 1
- 235000003702 sterols Nutrition 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000004575 stone Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 230000035882 stress Effects 0.000 description 1
- 230000002739 subcortical effect Effects 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000009469 supplementation Effects 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000005062 synaptic transmission Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 229940037128 systemic glucocorticoids Drugs 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940033134 talc Drugs 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229960004072 thrombin Drugs 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 239000003204 tranquilizing agent Substances 0.000 description 1
- 230000002936 tranquilizing effect Effects 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 229940078499 tricalcium phosphate Drugs 0.000 description 1
- 229910000391 tricalcium phosphate Inorganic materials 0.000 description 1
- 235000019731 tricalcium phosphate Nutrition 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 229940116269 uric acid Drugs 0.000 description 1
- 230000004855 vascular circulation Effects 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- 230000002227 vasoactive effect Effects 0.000 description 1
- 239000005526 vasoconstrictor agent Substances 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- NLVXSWCKKBEXTG-UHFFFAOYSA-N vinylsulfonic acid Chemical compound OS(=O)(=O)C=C NLVXSWCKKBEXTG-UHFFFAOYSA-N 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229940100445 wheat starch Drugs 0.000 description 1
- 239000003357 wound healing promoting agent Substances 0.000 description 1
- 239000003064 xanthine oxidase inhibitor Substances 0.000 description 1
- 229940093612 zein Drugs 0.000 description 1
- 239000005019 zein Substances 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
- 229960002769 zofenopril Drugs 0.000 description 1
- IAIDUHCBNLFXEF-MNEFBYGVSA-N zofenopril Chemical compound C([C@@H](C)C(=O)N1[C@@H](C[C@@H](C1)SC=1C=CC=CC=1)C(O)=O)SC(=O)C1=CC=CC=C1 IAIDUHCBNLFXEF-MNEFBYGVSA-N 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/225—Polycarboxylic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Emergency Medicine (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Coloring Foods And Improving Nutritive Qualities (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
本出願は、米国仮特許出願第60/421,258号、発明の名称「脳血管および心臓血管の疾患および障害を治療するための方法および組成物」(2002年10月24日出願)、米国仮特許出願第60/507,312号、発明の名称「脳血管および心臓血管の疾患および障害を治療するための方法および組成物」(2003年9月29日出願)、および米国仮特許出願第60/XXX,XXX号、発明の名称「徐放性L−アルギニン製剤並びに製造方法および使用方法」(2003年10月17日出願)に対して優先権を主張する。上記仮出願それぞれの開示内容は、その全内容が本明細書に援用される。
一酸化窒素合成酵素(NOS)と呼ばれる酵素のファミリーは、重要な生物学的2次メッセンジャーである一酸化窒素(NO)をL−アルギニンから合成する。NOSには複数の異なるアイソフォームがあり、例えば、構成型NOS(cNOS)と誘導型NOS(iNOS)が挙げられる。cNOSには、内皮型NOS(eNOS)と神経型NOS(nNOS)の異なる2種類が存在する。eNOSは、平滑筋弛緩の調節、血圧の降下および血小板凝集の阻害に関与する。eNOSは内皮細胞に存在し、レセプター介在型の細胞内Ca2+上昇に応答してNOを短期間放出する。Michelら、「一酸化窒素合成:何が、どこで、どのように、そして何故?」J.Clin.Invest 100:2146−2152(1997)。nNOSは長期間にわたる増強に重要であり、ニューロンからのCa2+依存性放出を担っている。iNOSは宿主防御において作用し、活性化マクロファージ細胞によって免疫応答時に産生され、血管平滑筋細胞で(例えば、各種サイトカイン、微生物産物および/または細菌内毒素によって)誘導され、また、一旦発現するとNOを長期間にわたって合成する。
本発明は、心臓血管、脳血管および末梢血管の疾患および障害が挙げられるが、これらに限定されない血管疾患および血管障害を治療および予防する方法を提供する。本発明は、HMG−CoA還元酵素阻害剤とL−アルギニンの徐放性製剤との同時投与が、血管疾患および血管障害の治療および予防、特にコレステロールおよび中性脂肪の低減において相乗作用を示すという発見に少なくとも一部基づくものである。また、本発明は、L−アルギニンの徐放性製剤、および組成物に最適な放出プロファイルを付与する製造方法を提供する。さらに、前記製剤および製造方法は、簡便に圧縮可能であるが脆過ぎることのない組成物をもたらすものである。
本発明は、心臓血管、脳血管および末梢血管の疾患および障害が挙げられるが、これらに限定されない血管疾患および血管障害を治療および予防する方法を提供する。本発明は、HMG−CoA還元酵素阻害剤とL−アルギニンの徐放性製剤との同時投与が、血管疾患および血管障害(脳血管、心臓血管および末梢血管の疾患または障害を含む)の治療および予防、特にコレステロールの低減において驚くべき相乗作用を示すとうい発見に少なくとも一部基づくものである。また、徐放性L−アルギニンと、場合によってはHMG−CoA還元酵素阻害剤とを使用して、血管拡張を増加させ、NO産生を増加させ、かつ、C−反応性タンパク質を低下させることも可能である。別の実施形態では、本明細書に記載の製剤および方法を使用して、例えば、血管疾患もしくは血管障害の発症および/または事象の発生の危険性がある集団において、疾患、障害および/または事象の発症を遅らせることも可能である。HMG−CoA還元酵素阻害剤とL−アルギニンの徐放性製剤は、続けてまたは同時に被験者へ投与することができる。前記還元酵素阻害剤およびL−アルギニンは、1つの製剤中へ含有させてもよい。
本発明のさらなる記述に先立ち、本明細書、実施例および特許請求の範囲中で使用する特定の用語を、便宜上ここに集める。
用語「天然型NO」とは、本明細書中では、L−アルギニンの生体内変換またはL−アルギニン依存性経路によって産生される一酸化窒素をいう。用語「内皮由来弛緩因子(EDRF)」または「内皮由来一酸化窒素(EDNO)」は、「天然型NO」と区別なく用いることができる。
本明細書中では、用語「剤形」とは、被験者、例えば患者への単回投与または複数回投与に見合った量の有効成分を含有する医薬組成物を意味する。
本明細書中では、特に記載しない限り、用語「半減期」とは、生物の血漿中の薬物濃度を投与時の薬物濃度の約半分に低下させるのに要する時間を意味する。
本明細書中では、用語「医薬組成物」または「医薬製剤」とは、双方とも区別なく使用されるが、薬学的に許容し得る成分を含む組成物を意味する。
本明細書中では、特にことわらない限り、用語「徐放」は、薬物が一定の期間放出されるような、1種以上の薬物の持続放出パターンと定義する。本発明の目的には、徐放と制御放出とを区別なく使用する。
以下の小節では、本発明の各種態様をさらに詳細に記載する。
本発明の方法は、被験者にHMG−CoA還元酵素阻害剤を含む製剤とL−アルギニンを含む製剤とを同時にまたは続けて投与することを含む、被験者、例えばヒトの脳血管および/または心臓血管の疾患または障害を治療および予防する方法を含む。あるいは、L−アルギニンとHMG−CoA還元酵素阻害剤とを含む単一の製剤を被験者に投与する。
1つの態様では、本発明は、脳血管および/または心臓血管の疾患または障害の危険性のある被験者に、L−アルギニンを含む製剤とHMG−CoA還元酵素阻害剤(例えばシンバスタチン)を含む製剤とを続けてまたは同時に投与するか、あるいはL−アルギニンとHMG−CoA還元酵素阻害剤とを含む単一の製剤を投与することにより、被験者の血管疾患または血管障害、例えば脳血管および/または心臓血管の疾患または障害を予防する方法を提供する。脳血管および/または心臓血管の疾患または障害(事象を含む)の危険性のある被験者は、例えば、アテローム硬化症に対する素因、アテローム硬化症の症状、または、例えば喫煙、高血圧、糖尿病、家族歴、遺伝的要因、高コレステロールレベル、加齢およびアルコール摂取等の危険因子の有無などにより特定できる。
L−アルギニン顆粒をマトリックス内へ効率的かつ実質的に封入または被覆することにより、本発明の組成物の徐放特性が向上することが判明した。セルロース系マトリックスの場合には、水と接触すると、マトリックスは一部水和してL−アルギニンの放出速度を制御するゲル層を形成する。L−アルギニン顆粒を効率的に被覆または封入することで、溶解に対して一過性のバリアを作り、L−アルギニンの送達を持続させる。マトリックス中にはかなりの間隙があるため、L−アルギニンは急速に溶解してしまう。本発明の方法では、直接圧粉で製造した製品よりも特性の向上した製品が得られる。さらに、本発明の方法は、流動化分散(fluidization dispersions)を含む方法(これらの方法は時間と費用がかかる)よりも有利である。
乾式造粒とは、熱および溶剤を用いない処方物の造粒をいう。乾式造粒技術としては、一般にスラッギングやロール圧粉が挙げられる。スラッギングは、処方物を乾式配合し、処方物を圧縮機上で大型の錠剤またはスラグへ圧縮することからなる。得られた錠剤またはスラグを磨砕して顆粒を得る。ローラー圧粉はスラッギングに似ているが、ローラー圧粉では、打錠機の代わりにローラー圧粉機を使用する。例えば、医薬造粒技術ハンドブック、D.M.Parikh編、Marcel−Dekker,Inc.、102−103頁(1997)を参照のこと。乾式造粒技術は特定の場合、例えば、活性物質が熱または溶剤の影響を受けやすい場合に有用である。
本発明の製剤を製造する特定の処方および方法は、徐放性L−アルギニン組成物に独特の利点を付与する。特に、本発明の製剤および方法は、望ましい徐放溶解プロファイルを達成する組成物をもたらす。最適には、徐放性L−アルギニン製剤は、in vitroでの薬物放出を少なくとも14時間まで持続させるものであり、好ましくは、約1時間で約10%〜約40%、約4時間で約30%〜約70%、約6時間で約55%〜約75%、約8時間で約65%〜約85%、約12時間で約75%〜約95%、14時間で約80%〜約100%が放出される。図7から明らかなように、本発明の製剤はこのような最適な溶解を達成する。さらに、実施例8および実施例14に示すように、溶解および安定性の試験からは、本発明の製剤が、製造の1ヵ月および2ヵ月後に最適な溶解プロファイルを示すことが明らかである。
約250gのL−アルギニンをミキサーに入れ、100rpmにてゆっくり混合しながら100gのユードラジットRS 30D低透過性メタクリル酸水性ポリマー分散液(ローム・アメリカ、ピスカタウェイ、ニュージャージー州)を添加して湿潤塊を形成した。湿潤塊を18−20篩に通し、50℃で24時間乾燥させた。得られた乾燥L−アルギニン粒状物(250g)を84gのメトセルK100 M CRメチルセルロース(ダウ・ケミカル社、ダンベリー、コネティカット州)および3gのステアリン酸マグネシウムと共に乾式混合し、配合物を形成した。得られた配合物を圧縮し、7/16凹形パンチを用いて錠剤とした。
250gのL−アルギニンをミキサーに入れ、ゆっくり混合しながら84gのメトセルK100 M CRメチルセルロースおよび3gのステアリン酸マグネシウムを添加した。得られた配合物を圧縮し、7/16凹形パンチを用いて錠剤とした。
250gのL−アルギニンをミキサーに入れ、ゆっくり混合しながら100gのユードラジットRS 30D低透過性メタクリル酸水性ポリマー分散液を添加して湿潤塊を形成した。湿潤塊を18−20篩に通し、50℃で24時間乾燥させた。得られた乾燥L−アルギニン粒状物(250g)を84gのメトセルK100 M CRメチルセルロースおよび3gのステアリン酸マグネシウムと共に乾式混合し、配合物を形成した。得られた配合物を00号ゲルカプセルへ封入した。
250gのL−アルギニンをミキサーに入れ、ゆっくり混合しながら84gのメトセルK100 M CRメチルセルロースおよび3gのステアリン酸マグネシウムを添加した。得られた配合物を00号ゲルカプセルへ封入した。
250gのL−アルギニンおよび50gのメトセルK100 M CRメチルセルロースを混合し、キッチンエイド(登録商標)ミキサーを用いて低速で10分間均質化し、乾燥配合物を形成した。この乾燥配合物に、115gのユードラジットRS 30D低透過性メタクリル酸水性ポリマー分散液を5gずつ塊が均一に湿潤するまで添加した。湿潤塊を12メッシュの篩、次いで20メッシュの篩に通し、その後、水分含有量が1重量%になるまで30℃で24時間乾燥させた。得られた乾燥L−アルギニン粒状物を7gのステアリン酸マグネシウムと乾式混合し、次いでマネスティー ベータプレスを用いて圧縮し、7/16凹形パンチを用いて錠剤とした。
約1000gのL−アルギニンおよび約200gのメトセルK100 M CRメチルセルロースをGP−1高剪断ミキサー(造粒機)内で約5分間100rpmにて混合した。次いで約138gのユードラジットRS 30D低透過性メタクリル酸水性ポリマー分散液を、200rpmおよび1.5バールの圧力でインペラーを動かしながら添加した。混合物を1分間200rpmにて造粒した。次いで造粒物を、MP−1流動床造粒機内で45℃の入口温度、100CMHの風量にておよそ2%の水分含有量まで乾燥させた。次いで乾燥顆粒を、サイズ55Rスクリーンおよび円形インペラーを備えたComil197Sを用いて90%の速度で磨砕した。8クォートV−ブレンダー内にて、約27gのステアリン酸マグネシウムを磨砕後の顆粒に添加し、2分間混合した。次いでこの材料を、7/16”の標準的な凹形の成形型を備えたマネスティー ベータプレスを用いて可能な最高硬度まで圧縮し、目標重量682.5mgの錠剤とした。錠剤を75ccのHDPEボトルに手作業で包装した(ボトル当たり60錠)。
L−アルギニンの徐放性錠剤対即時放出カプセル剤の薬物動態を評価するため、無作為4元クロスオーバー試験(crossover study)を14人の健常成人被験者に絶食条件下で行った。本明細書中、「健常」とは、心臓血管危険因子をもたない高コレステロール血症ではない被験者を意味する。本試験では、実施例6の徐放性L−アルギニン錠剤(L−アルギニンSR)と、Montiff(ロサンゼルス、CA)より購入した市販の即時放出L−アルギニンカプセル剤(L−アルギニンIR)とを比較した。
表IIに、改良型徐放性錠剤を製造するために集めた成分、および各成分の使用量を示す。
L−アルギニンSR(シンバスタチン有り、なし)とシンバスタチン(L−アルギニンSR有り、なし)の薬物動態を検討した。実施例6のL−アルギニンSR錠剤、およびBioEnergy(ウォレン、ニュージャージー州)より購入した市販のシンバスタチン錠剤を使用した。
梗塞サイズに及ぼすシンバスタチンおよびL−アルギニン双方の投与の効果をマウスで検討した。マウスには、生理食塩溶液に図3に示す量で溶解したシンバスタチン、およびシンバスタチン+L−アルギニンを含む腹腔注射剤を投与した。これらマウスの梗塞サイズの結果(対照群と比較)を図2および図3に示す。
シンバスタチンとL−アルギニンとの併用投与の用量最適化をマウスで検討した。マウスには、図4に示すようにシンバスタチンおよびL−アルギニンのレベルを変えて注射した。本検討の結果も図4に示す。統計解析より、最適な併用範囲は1.2〜1.4mg/Kgのシンバスタチンと約20〜25mg/KgのL−アルギニンであると予測された。
スタチン類は、in vitroでは内皮NO合成酵素(eNOS)の発現を刺激し、in vivoでは内皮依存性のNO介在型血管拡張を亢進する。非対称性ジメチルアルギニン(ADMA)はeNOSの内在性競合阻害剤である。血漿ADMAレベルの上昇には内皮機能不全が伴う。ADMAの阻害作用がL−アルギニン徐放性製剤の補足によって解消される場合に限り、ADMAが上昇した患者の内皮機能がシンバスタチンによって亢進されることが判明した。
実施例12に記載の試験において、総コレステロール(TC)、LDLコレステロール、HDLコレステロールおよび中性脂肪の変化を治療の前後で分析した。本分析の結果を図9に示す。結果から明らかなように、本発明の徐放性L−アルギニンとシンバスタチンとの同時投与により、シンバスタチンの単独投与よりも大幅に、総コレステロール、LDLコレステロールおよび中性脂肪が低下し、HDLコレステロールが増加する。
移動相を以下のように調製した。まず、約0.9gの1−ペンタンスルホン酸ナトリウム塩一水和物および3.5gのリン酸二水素ナトリウム一水和物を適当な容器に計り取り、1リットルのpH3.3緩衝溶液を調製した。約100mLの脱イオン水を添加して溶解した。リン酸を添加してpHを3.3に調整した。続いて、850mLのpH3.3緩衝液を150mLのメタノールと合わせて適当な容器に入れ、混合した。混合物を0.45μmのナイロンメンブランフィルターで濾過した。最後に、混合物を使用前に脱気した。
T=W.05/2f
式中、W.05はベースラインから5%のピーク高におけるアルギニンHClピークのピーク幅であり、fはピークの極大からピークの立ち上りまでの距離であり、前記距離はベースラインから5%のピーク高の地点で測定。
下記のプロトコールを使用して、シンバスタチンに依存するeNOS機能の増加機構を培養ヒト大動脈内皮細胞(HAEC)を用いて検討し、eNOS機能のアップレギュレーションにおいて、タンパク質のde novo合成と、タンパク質の移動または活性化とを区別した。
等価事例
当業者であれば、通常の実験の範囲内で、本明細書に記載した本発明の具体的な実施形態に相当する多くの等価事例を認識し、確認することが可能である。このような等価事例は特許請求の範囲内に含まれるものとする。
Claims (93)
- 被験者のコレステロールを低下させる方法であって、被験者にHMG−CoA還元酵素阻害剤とL−アルギニンを含む徐放性製剤とを投与することを含む、前記方法。
- HMG−CoA還元酵素阻害剤が徐放性製剤を構成している、請求項1記載の方法。
- 被験者の総コレステロールおよび低密度リポタンパク質(LDL)コレステロールを低下させる、請求項1記載の方法。
- HMG−CoA還元酵素阻害剤がシンバスタチンを含む、請求項1記載の方法。
- 総コレステロールを約50〜約150mg/dL低下させる、請求項1記載の方法。
- 総コレステロールを約80〜約100mg/dL低下させる、請求項1記載の方法。
- LDLコレステロールを約40〜約110mg/dL低下させる、請求項1記載の方法。
- LDLコレステロールを約60〜約100mg/dL低下させる、請求項1記載の方法。
- 被験者の高密度リポタンパク質(HDL)コレステロールを増加させる、請求項1記載の方法。
- 中性脂肪を約30〜約100mg/dL低下させる、請求項1記載の方法。
- 中性脂肪を約45〜約75mg/dL低下させる、請求項1記載の方法。
- 被験者にHMG−CoA還元酵素阻害剤を投与する際にL−アルギニンを含む徐放性製剤を併用しない場合よりも、総コレステロールを約5%〜約15%多く低下させる、請求項1記載の方法。
- 被験者にHMG−CoA還元酵素阻害剤を投与する際にL−アルギニンを含む徐放性製剤を併用しない場合よりも、総コレステロールを少なくとも約5〜約20mg/dL多く低下させる、請求項1記載の方法。
- 被験者にHMG−CoA還元酵素阻害剤を投与する際にL−アルギニンを含む徐放性製剤を併用しない場合よりも、LDLコレステロールを少なくとも約2〜約20mg/dL多く低下させる、請求項1記載の方法。
- 被験者にHMG−CoA還元酵素阻害剤を投与する際にL−アルギニンを含む徐放性製剤を併用しない場合よりも、中性脂肪を少なくとも約5〜約50mg/dL多く低下させる、請求項1記載の方法。
- 被験者にHMG−CoA還元酵素阻害剤を投与する際にL−アルギニンを含む徐放性製剤を併用しない場合よりも、中性脂肪を少なくとも約20〜約35mg/dL多く低下させる、請求項1記載の方法。
- 非対称性ジメチルアルギニン(ADMA)が上昇している被験者において一酸化窒素産生を増加させる方法であって、被験者にHMG−CoA還元酵素阻害剤とL−アルギニンとを投与することを含む、前記方法。
- 非対称性ジメチルアルギニン(ADMA)が上昇している被験者において血管拡張を増加させる方法であって、被験者にHMG−CoA還元酵素阻害剤とL−アルギニンとを投与することを含む、前記方法。
- HMG−CoA還元酵素阻害剤がシンバスタチンを含む、請求項17または18記載の方法。
- L−アルギニンが徐放性製剤を構成している、請求項17または18記載の方法。
- 内皮機能を少なくとも約5〜約15%増加させる、請求項17または18記載の方法。
- 内皮機能を少なくとも約7〜約12%増加させる、請求項17または18記載の方法。
- 被験者が内皮機能不全を有する、請求項17または18記載の方法。
- 被験者にL−アルギニンを投与することを含む、非対称性ジメチルアルギニン(ADMA)が上昇している被験者において一酸化窒素(NO)産生を増加させる方法であって、L−アルギニンによってADMAの阻害作用を解消する、前記方法。
- 被験者にL−アルギニンを投与することを含む、非対称性ジメチルアルギニン(ADMA)が上昇している被験者において血管拡張を増加させる方法であって、L−アルギニンによってADMAの阻害作用を解消する、前記方法。
- 被験者が内皮機能不全を有する、請求項24または25記載の方法。
- L−アルギニンが徐放性製剤を構成している、請求項24または25記載の方法。
- 内皮機能を約5%〜約15%増加させる、請求項24または25記載の方法。
- 内皮機能を約6%〜約10%増加させる、請求項24または25記載の方法。
- 被験者にHMG−CoA還元酵素阻害剤を投与することをさらに含む、請求項24または25記載の方法。
- HMG−CoA還元酵素阻害剤がシンバスタチンを含む、請求項30記載の方法。
- HMG−CoA還元酵素阻害剤とL−アルギニンとを投与することにより、内皮機能を約5%〜約15%増加させる、請求項30記載の方法。
- HMG−CoA還元酵素阻害剤とL−アルギニンとを投与することにより、内皮機能を約7%〜約12%増加させる、請求項30記載の方法。
- 徐放性L−アルギニン組成物であって:
(a)約25〜約75重量%のL−アルギニンまたはその薬学的に許容し得る塩;
(b)約0.5〜約5重量%のポリビニルピロリドン;
(c)約5〜約40重量%のヒドロキシプロピルメチルセルロース;
(d)約2〜約20重量%の微結晶セルロース;
(e)約3重量%未満の二酸化ケイ素;および
(f)約3重量%未満のステアリン酸マグネシウム、
を含む、前記組成物。 - (a)約50重量%のL−アルギニン一塩酸塩(ここで、L−アルギニンはL−アルギニン一塩酸塩を含む);
(b)約3〜約4重量%のポリビニルピロリドン;
(c)約35重量%のヒドロキシプロピルメチルセルロース;
(d)約10重量%の微結晶セルロース;
(e)約1重量%未満のコロイド状二酸化ケイ素(ここで、二酸化ケイ素はコロイド状二酸化ケイ素を含む);および
(f)約1重量%未満のステアリン酸マグネシウム、
を含む、請求項34記載の組成物。 - L−アルギニンの徐放性組成物を製造する方法であって、
(a)L−アルギニンを造粒剤で造粒して顆粒を形成し;
(b)顆粒を湿式磨砕し;
(c)顆粒を乾燥させ;
(d)顆粒を乾式磨砕し;
(e)顆粒を少なくとも1種の徐放剤と配合する、
ことを含む、前記方法。 - 工程(e)が、顆粒を予備配合、配合および最終配合する工程を含む、請求項36記載の方法。
- 造粒工程に先立ち、L−アルギニンを結合剤と乾式混合することをさらに含む、請求項36記載の方法。
- 結合剤がポリビニルピロリドンを含む、請求項38記載の方法。
- (a)L−アルギニンを、ポリビニルピロリドンを含む造粒剤で造粒し(ここで、L−アルギニンは徐放性製剤の約50重量%、ポリビニルピロリドンは徐放性製剤の約3〜約4重量%を構成する);
(b)顆粒を湿式磨砕し;
(c)顆粒を乾燥させ;
(d)顆粒を乾式磨砕し;
(e)顆粒をヒドロキシプロピルメチルセルロースと配合する(ここで、ヒドロキシプロピルメチルセルロースは徐放性製剤の約35重量%を構成する)、
ことを含む、請求項36記載の方法。 - 顆粒を微結晶セルロース、コロイド状二酸化ケイ素およびステアリン酸マグネシウムと配合する(ここで、微結晶セルロースは徐放性製剤の約10重量%、コロイド状二酸化ケイ素は徐放性製剤の約1%未満、ステアリン酸マグネシウムは徐放性製剤の約1重量%未満を構成する)ことをさらに含む、請求項40記載の方法。
- L−アルギニンを含む徐放性製剤を含む、血管疾患もしくは血管障害の治療または予防に使用する棒状食品。
- 徐放性製剤がL−アルギニンの徐放性粒状物を含む、請求項42記載の棒状食品。
- HMG−CoA還元酵素阻害剤をさらに含む、請求項42記載の棒状食品。
- 被験者が摂取するとコレステロールを低下させる、請求項42記載の棒状食品。
- アルツハイマー病の治療または予防に使用される、請求項42記載の棒状食品。
- 間欠性跛行の治療または予防に使用される、請求項42記載の棒状食品。
- 被験者が摂取するとC−反応性タンパク質を低下させる、請求項42記載の棒状食品。
- 被験者の血管疾患もしくは血管障害を予防または治療する方法であって、被験者にL−アルギニンを含む徐放性製剤を含む棒状食品を与えることを含む、前記方法。
- 被験者のコレステロールを低下させる方法であって、被験者にL−アルギニンを含む徐放性製剤を含む棒状食品を与えることを含む、前記方法。
- 被験者の一酸化窒素を増加させる方法であって、被験者にL−アルギニンを含む徐放性製剤を含む棒状食品を与えることを含む、前記方法。
- 被験者の血管拡張を増加させる方法であって、被験者にL−アルギニンを含む徐放性製剤を含む棒状食品を与えることを含む、前記方法。
- 被験者のアルツハイマー病を治療または予防する方法であって、被験者にL−アルギニンを含む徐放性製剤を含む棒状食品を与えることを含む、前記方法。
- 被験者の間欠性跛行を治療または予防する方法であって、被験者にL−アルギニンを含む徐放性製剤を含む棒状食品を与えることを含む、前記方法。
- 被験者のC−反応性タンパク質を低下させる方法であって、被験者にL−アルギニンを含む徐放性製剤を含む棒状食品を与えることを含む、前記方法。
- 棒状食品がHMG−CoA還元酵素阻害剤をさらに含む、請求項49〜54のいずれか一項に記載の方法。
- HMG−CoA還元酵素阻害剤がシンバスタチンを含む、請求項56記載の方法。
- 被験者のコレステロールを低下させる方法であって、被験者にL−アルギニンを含む徐放性製剤を投与することを含む、前記方法。
- 被験者の総コレステロールおよび低密度リポタンパク質(LDL)コレステロールを低下させる、請求項58記載の方法。
- 総コレステロールを約50〜約150mg/dL低下させる、請求項58記載の方法。
- 総コレステロールを約80〜約100mg/dL低下させる、請求項58記載の方法。
- LDLコレステロールを約40〜約110mg/dL低下させる、請求項58記載の方法。
- LDLコレステロールを約60〜約100mg/dL低下させる、請求項58記載の方法。
- 被験者の高密度リポタンパク質(HDL)コレステロールを増加させる、請求項58記載の方法。
- 中性脂肪を約30〜約100mg/dL低下させる、請求項58記載の方法。
- 中性脂肪を約45〜約75mg/dL低下させる、請求項58記載の方法。
- 徐放性製剤が、
(a)約25〜約75重量%のL−アルギニンまたはその薬学的に許容し得る塩;
(b)約0.5〜約5重量%のポリビニルピロリドン;
(c)約5〜約40重量%のヒドロキシプロピルメチルセルロース;
(d)約2〜約20重量%の微結晶セルロース;
(e)約3重量%未満の二酸化ケイ素;および
(f)約3重量%未満のステアリン酸マグネシウム、
を含む、請求項58記載の方法。 - 徐放性製剤が、
(a)約50重量%のL−アルギニン一塩酸塩(ここで、L−アルギニンはL−アルギニン一塩酸塩を含む);
(b)約3〜約4重量%のポリビニルピロリドン;
(c)約35重量%のヒドロキシプロピルメチルセルロース;
(d)約10重量%の微結晶セルロース;
(e)約1重量%未満のコロイド状二酸化ケイ素(ここで、二酸化ケイ素はコロイド状二酸化ケイ素を含む);および
(f)約1重量%未満のステアリン酸マグネシウム、
を含む、請求項67記載の方法。 - 血管疾患もしくは血管障害を治療または予防する方法であって、被験者に、
(a)約25〜約75重量%のL−アルギニンまたはその薬学的に許容し得る塩;
(b)約0.5〜約5重量%のポリビニルピロリドン;
(c)約5〜約40重量%のヒドロキシプロピルメチルセルロース;
(d)約2〜約20重量%の微結晶セルロース;
(e)約3重量%未満の二酸化ケイ素;および
(f)約3重量%未満のステアリン酸マグネシウム、
を含む徐放性製剤を投与することを含む、前記方法。 - 徐放性製剤が、
(a)約50重量%のL−アルギニン一塩酸塩(ここで、L−アルギニンはL−アルギニン一塩酸塩を含む);
(b)約3〜約4重量%のポリビニルピロリドン;
(c)約35重量%のヒドロキシプロピルメチルセルロース;
(d)約10重量%の微結晶セルロース;
(e)約1重量%未満のコロイド状二酸化ケイ素(ここで、二酸化ケイ素はコロイド状二酸化ケイ素を含む);および
(f)約1重量%未満のステアリン酸マグネシウム、
を含む、請求項69記載の方法。 - アルツハイマー病を治療または予防する方法であって、被験者にL−アルギニンを含む徐放性製剤を投与することを含む、前記方法。
- 徐放性製剤が、
(a)約25〜約75重量%のL−アルギニンまたはその薬学的に許容し得る塩;
(b)約0.5〜約5重量%のポリビニルピロリドン;
(c)約5〜約40重量%のヒドロキシプロピルメチルセルロース;
(d)約2〜約20重量%の微結晶セルロース;
(e)約3重量%未満の二酸化ケイ素;および
(f)約3重量%未満のステアリン酸マグネシウム、
を含む、請求項71記載の方法。 - 徐放性製剤が、
(a)約50重量%のLアルギニン一塩酸塩(ここで、L−アルギニンはL−アルギニン一塩酸塩を含む);
(b)約3〜約4重量%のポリビニルピロリドン;
(c)約35重量%のヒドロキシプロピルメチルセルロース;
(d)約10重量%の微結晶セルロース;
(e)約1重量%未満のコロイド状二酸化ケイ素(ここで、二酸化ケイ素はコロイド状二酸化ケイ素を含む);および
(f)約1重量%未満のステアリン酸マグネシウム、
を含む、請求項72記載の方法。 - 間欠性跛行を治療または予防する方法であって、被験者にL−アルギニンを含む徐放性製剤を投与することを含む、前記方法。
- 徐放性製剤が、
(a)約25〜約75重量%のL−アルギニンまたはその薬学的に許容し得る塩;
(b)約0.5〜約5重量%のポリビニルピロリドン;
(c)約5〜約40重量%のヒドロキシプロピルメチルセルロース;
(d)約2〜約20重量%の微結晶セルロース;
(e)約3重量%未満の二酸化ケイ素;および
(f)約3重量%未満のステアリン酸マグネシウム、
を含む、請求項74記載の方法。 - 徐放性製剤が、
(a)約50重量%のL−アルギニン一塩酸塩(ここで、L−アルギニンはL−アルギニン一塩酸塩を含む);
(b)約3〜約4重量%のポリビニルピロリドン;
(c)約35重量%のヒドロキシプロピルメチルセルロース;
(d)約10重量%の微結晶セルロース;
(e)約1重量%未満のコロイド状二酸化ケイ素(ここで、二酸化ケイ素はコロイド状二酸化ケイ素を含む);および
(f)約1重量%未満のステアリン酸マグネシウム、
を含む、請求項75記載の方法。 - 被験者のアテローム硬化症を治療または予防する方法であって、被験者に、
(a)約25〜約75重量%のL−アルギニンまたはその薬学的に許容し得る塩;
(b)約0.5〜約5重量%のポリビニルピロリドン;
(c)約5〜約40重量%のヒドロキシプロピルメチルセルロース;
(d)約2〜約20重量%の微結晶セルロース;
(e)約3重量%未満の二酸化ケイ素;および
(f)約3重量%未満のステアリン酸マグネシウム、
を含む徐放性製剤を投与することを含む、前記方法。 - 徐放性製剤が、
(a)約50重量%のL−アルギニン一塩酸塩(ここで、L−アルギニンはL−アルギニン一塩酸塩を含む);
(b)約3〜約4重量%のポリビニルピロリドン;
(c)約35重量%のヒドロキシプロピルメチルセルロース;
(d)約10重量%の微結晶セルロース;
(e)約1重量%未満のコロイド状二酸化ケイ素(ここで、二酸化ケイ素はコロイド状二酸化ケイ素を含む);および
(f)約1重量%未満のステアリン酸マグネシウム、
を含む、請求項77記載の方法。 - 被験者の血管拡張を増加させる方法であって、被験者に、
(a)約25〜約75重量%のL−アルギニンまたはその薬学的に許容し得る塩;
(b)約0.5〜約5重量%のポリビニルピロリドン;
(c)約5〜約40重量%のヒドロキシプロピルメチルセルロース;
(d)約2〜約20重量%の微結晶セルロース;
(e)約3重量%未満の二酸化ケイ素;および
(f)約3重量%未満のステアリン酸マグネシウム、
を含む徐放性製剤を投与することを含む、前記方法。 - 徐放性製剤が、
(a)約50重量%のL−アルギニン一塩酸塩(ここで、L−アルギニンはL−アルギニン一塩酸塩を含む);
(b)約3〜約4重量%のポリビニルピロリドン;
(c)約35重量%のヒドロキシプロピルメチルセルロース;
(d)約10重量%の微結晶セルロース;
(e)約1重量%未満のコロイド状二酸化ケイ素(ここで、二酸化ケイ素はコロイド状二酸化ケイ素を含む);および
(f)約1重量%未満のステアリン酸マグネシウム、
を含む、請求項79記載の方法。 - 被験者の一酸化窒素産生を増加させる方法であって、被験者に、
(a)約25〜約75重量%のL−アルギニンまたはその薬学的に許容し得る塩;
(b)約0.5〜約5重量%のポリビニルピロリドン;
(c)約5〜約40重量%のヒドロキシプロピルメチルセルロース;
(d)約2〜約20重量%の微結晶セルロース;
(e)約3重量%未満の二酸化ケイ素;および
(f)約3重量%未満のステアリン酸マグネシウム、
を含む徐放性製剤を投与することを含む、前記方法。 - 徐放性製剤が、
(a)約50重量%のL−アルギニン一塩酸塩(ここで、L−アルギニンはL−アルギニン一塩酸塩を含む);
(b)約3〜約4重量%のポリビニルピロリドン;
(c)約35重量%のヒドロキシプロピルメチルセルロース;
(d)約10重量%の微結晶セルロース;
(e)約1重量%未満のコロイド状二酸化ケイ素(ここで、二酸化ケイ素はコロイド状二酸化ケイ素を含む);および
(f)約1重量%未満のステアリン酸マグネシウム、
を含む、請求項81記載の方法。 - C−反応性タンパク質を低下させる方法であって、L−アルギニンを被験者に投与することを含む、前記方法。
- L−アルギニンが徐放性製剤を構成している、請求項83記載の方法。
- 徐放性製剤が、
(a)約25〜約75重量%のL−アルギニンまたはその薬学的に許容し得る塩;
(b)約0.5〜約5重量%のポリビニルピロリドン;
(c)約5〜約40重量%のヒドロキシプロピルメチルセルロース;
(d)約2〜約20重量%の微結晶セルロース;
(e)約3重量%未満の二酸化ケイ素;および
(f)約3重量%未満のステアリン酸マグネシウム、
を含む、請求項83記載の方法。 - 徐放性製剤が、
(a)約50重量%のL−アルギニン一塩酸塩(ここで、L−アルギニンはL−アルギニン一塩酸塩を含む);
(b)約3〜約4重量%のポリビニルピロリドン;
(c)約35重量%のヒドロキシプロピルメチルセルロース;
(d)約10重量%の微結晶セルロース;
(e)約1重量%未満のコロイド状二酸化ケイ素(ここで、二酸化ケイ素はコロイド状二酸化ケイ素を含む);および
(f)約1重量%未満のステアリン酸マグネシウム、
を含む、請求項85記載の方法。 - 被験者のC−反応性タンパク質を低下させる方法であって、被験者にHMG−CoA還元酵素阻害剤とL−アルギニンを含む徐放性製剤とを投与することを含む、前記方法。
- C−反応性タンパク質を約10%〜約50%低下させる、請求項87記載の方法。
- C−反応性タンパク質を約25%〜約35%低下させる、請求項87記載の方法。
- 被験者にHMG−CoA還元酵素阻害剤を投与する際にL−アルギニンを含む徐放性製剤を併用しない場合よりも、C−反応性タンパク質を約50%〜約90%多く低下させる、請求項87記載の方法。
- 被験者にHMG−CoA還元酵素阻害剤を投与する際にL−アルギニンを含む徐放性製剤を併用しない場合よりも、C−反応性タンパク質を約65%〜約75%多く低下させる、請求項87記載の方法。
- 被験者にL−アルギニンを含む徐放性製剤を投与する際にHMG−CoA還元酵素阻害剤を併用しない場合よりも、C−反応性タンパク質を約80%〜約120%多く低下させる、請求項87記載の方法。
- 被験者にL−アルギニンを含む徐放性製剤を投与する際にHMG−CoA還元酵素阻害剤を併用しない場合よりも、C−反応性タンパク質を約95%〜約105%多く低下させる、請求項87記載の方法。
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US42125802P | 2002-10-24 | 2002-10-24 | |
US50731203P | 2003-09-29 | 2003-09-29 | |
US51203503P | 2003-10-17 | 2003-10-17 | |
PCT/US2003/033931 WO2004037203A2 (en) | 2002-10-24 | 2003-10-24 | Sustained release l-arginine formulations and methods of manufacture and use |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2006514100A true JP2006514100A (ja) | 2006-04-27 |
JP2006514100A5 JP2006514100A5 (ja) | 2006-12-14 |
Family
ID=32180509
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2005501690A Withdrawn JP2006514100A (ja) | 2002-10-24 | 2003-10-24 | 徐放性l−アルギニン製剤並びに製造方法および使用方法 |
Country Status (9)
Country | Link |
---|---|
US (1) | US20050287210A1 (ja) |
EP (1) | EP1562555A2 (ja) |
JP (1) | JP2006514100A (ja) |
KR (1) | KR20050083827A (ja) |
AU (1) | AU2003284962B2 (ja) |
CA (1) | CA2503284A1 (ja) |
MX (1) | MXPA05004290A (ja) |
NZ (1) | NZ539672A (ja) |
WO (1) | WO2004037203A2 (ja) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2015533134A (ja) * | 2012-10-09 | 2015-11-19 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 錠剤の機械的安定性に適切な少なくとも1種の水和物形成活性物質及び/又はアジュバントを含有する機械的に安定な錠剤、特にアルギニン含有錠剤の製造における選択的に水分調整された打錠材料の使用 |
Families Citing this family (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20110196039A9 (en) * | 1994-10-05 | 2011-08-11 | Kaesemeyer Wayne H | Controlled release arginine formulations |
US20040253305A1 (en) * | 2003-06-12 | 2004-12-16 | Luner Paul E. | Pharmaceutical compositions of atorvastatin |
JP2007521324A (ja) * | 2003-09-29 | 2007-08-02 | エノス ファーマシューティカルズ, インク. | 徐放性l−アルギニン調合物並びにその製造法及び使用法 |
EP1846037A4 (en) * | 2005-01-24 | 2008-03-12 | Palmetto Pharmaceuticals Llc | METHODS OF TREATING VARIOUS CONDITIONS BY ADMINISTERING L-ARGININE WITH PROLONGED RELEASE |
WO2007070454A2 (en) * | 2005-12-09 | 2007-06-21 | Novalife | High protein supplement |
US7982066B2 (en) | 2005-12-09 | 2011-07-19 | Novalife, Inc. | High protein supplement |
CA2642761A1 (en) * | 2006-02-23 | 2007-08-30 | Iomedix Sleep International Srl | Compositions and methods for the induction and maintenance of quality sleep |
US8569368B2 (en) | 2007-09-18 | 2013-10-29 | Thermolife International, Llc | Amino acid compounds |
US8455531B2 (en) | 2007-09-18 | 2013-06-04 | Thermolife International, Llc | Amino acid compositions |
US7777074B2 (en) | 2007-09-18 | 2010-08-17 | Thermolife International, Llc | Amino acid compounds |
US10646508B1 (en) | 2007-09-18 | 2020-05-12 | Thermolife International, Llc | Method of safely administering nitrate dietary supplements and compositions |
US8466187B2 (en) | 2007-09-18 | 2013-06-18 | Thermolife International, Llc | Amino acid compositions |
US10435356B1 (en) | 2007-09-18 | 2019-10-08 | Thermolife International, Llc | Amino acid compositions |
US8569369B2 (en) | 2007-09-18 | 2013-10-29 | Thermolife International, Llc | Amino acid compounds |
US10426750B1 (en) | 2007-09-18 | 2019-10-01 | Thermolife International, Llc | Amino acid supplement formulations |
SG10201408384PA (en) * | 2009-12-18 | 2015-01-29 | Novartis Ag | Wash solution and method for affinity chromatography |
HUE032165T2 (en) | 2011-04-13 | 2017-09-28 | Thermolife Int Llc | Methods of using N-actyl-beta-alanine |
KR101953405B1 (ko) * | 2011-06-01 | 2019-02-28 | 노파르티스 아게 | 친화성 크로마토그래피를 위한 세척 용액 및 방법 |
US11865139B2 (en) | 2020-11-12 | 2024-01-09 | Thermolife International, Llc | Method of treating migraines and headaches |
Family Cites Families (90)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4008323A (en) * | 1974-03-25 | 1977-02-15 | Pierre Fabre S.A. | Method of reducing cholesterol using certain aromatic keto acids |
US4231938A (en) * | 1979-06-15 | 1980-11-04 | Merck & Co., Inc. | Hypocholesteremic fermentation products and process of preparation |
US4444784A (en) * | 1980-08-05 | 1984-04-24 | Merck & Co., Inc. | Antihypercholesterolemic compounds |
MX7065E (es) * | 1980-06-06 | 1987-04-10 | Sankyo Co | Un procedimiento microbiologico para preparar derivados de ml-236b |
US5366738A (en) * | 1982-07-29 | 1994-11-22 | Merck & Co., Inc. | Controlled release drug dispersion delivery device |
US4739073A (en) * | 1983-11-04 | 1988-04-19 | Sandoz Pharmaceuticals Corp. | Intermediates in the synthesis of indole analogs of mevalonolactone and derivatives thereof |
US4882167A (en) * | 1983-05-31 | 1989-11-21 | Jang Choong Gook | Dry direct compression compositions for controlled release dosage forms |
US4590062A (en) * | 1984-04-16 | 1986-05-20 | Tech Trade Corp. | Dry direct compression compositions for controlled release dosage forms |
US4629620A (en) * | 1984-09-05 | 1986-12-16 | Ab Ferrosan | Membrane-coated sustained-release tablets and method |
US4920098A (en) * | 1986-09-17 | 1990-04-24 | Baxter International Inc. | Nutritional support or therapy for individuals at risk or under treatment for atherosclerotic vascular, cardiovascular, and/or thrombotic diseases |
FI94339C (fi) * | 1989-07-21 | 1995-08-25 | Warner Lambert Co | Menetelmä farmaseuttisesti käyttökelpoisen /R-(R*,R*)/-2-(4-fluorifenyyli)- , -dihydroksi-5-(1-metyylietyyli)-3-fenyyli-4-/(fenyyliamino)karbonyyli/-1H-pyrroli-1-heptaanihapon ja sen farmaseuttisesti hyväksyttävien suolojen valmistamiseksi |
US5157022A (en) * | 1989-11-22 | 1992-10-20 | Adrian Barbul | Method for reducing blood cholesterol using arginine |
US5576351A (en) * | 1989-12-29 | 1996-11-19 | Mcgaw, Inc. | Use of arginine as an immunostimulator |
EP0441119A3 (en) * | 1990-01-09 | 1992-10-14 | Richard D. Levere | The use of l-arginine in the treatment of hypertension and other vascular disorders |
US5395612A (en) * | 1990-03-27 | 1995-03-07 | Cornell Research Foundation, Inc. | Method for treating systemic hypotension caused by sepsis or cytokine using arginase in combination with an α1 adrenergic agonist |
US5300288A (en) * | 1991-04-05 | 1994-04-05 | Rohm And Haas Company | Composition and method for controlling cholesterol |
US5145684A (en) * | 1991-01-25 | 1992-09-08 | Sterling Drug Inc. | Surface modified drug nanoparticles |
US5543154A (en) * | 1991-12-27 | 1996-08-06 | Merck & Co., Inc. | Controlled release nifedipine delivery device |
US6187744B1 (en) * | 1992-03-11 | 2001-02-13 | Michael W. Rooney | Methods and compositions for regulating the intravascular flow and oxygenating activity of hemoglobin in a human or animal subject |
ZA933359B (en) * | 1992-05-15 | 1993-12-08 | Sankyo Co | Octahydronaphthalene oxime derivatives for cholesterol biosynthesis inhibition, their preparation and use |
US5712396A (en) * | 1992-10-28 | 1998-01-27 | Magnin; David R. | α-phosphonosulfonate squalene synthetase inhibitors |
US5385940A (en) * | 1992-11-05 | 1995-01-31 | The General Hospital Corporation | Treatment of stroke with nitric-oxide releasing compounds |
US5326569A (en) * | 1992-12-23 | 1994-07-05 | Abbott Laboratories | Medical foods for the nutritional support of child/adult metabolic diseases |
US5945452A (en) * | 1993-06-11 | 1999-08-31 | The Board Of Trustees Of The Leland Stanford Junior University | Treatment of vascular degenerative diseases by modulation of endogenous nitric oxide production or activity |
US5428070A (en) * | 1993-06-11 | 1995-06-27 | The Board Of Trustees Of The Leland Stanford Junior University | Treatment of vascular degenerative diseases by modulation of endogenous nitric oxide production of activity |
US5861168A (en) * | 1993-06-11 | 1999-01-19 | The Board Of Trustees Of The Leland Stanford Junior University | Intramural delivery of nitric oxide enhancer for inhibiting lesion formation after vascular injury |
US5891459A (en) * | 1993-06-11 | 1999-04-06 | The Board Of Trustees Of The Leland Stanford Junior University | Enhancement of vascular function by modulation of endogenous nitric oxide production or activity |
US5895783A (en) * | 1993-07-16 | 1999-04-20 | Schering Aktiengesellschaft | Treatment of preeclampsia and preterm labor with combination of progestational agent and a nitric oxide synthase substrate and/or donor |
US5595970A (en) * | 1993-07-16 | 1997-01-21 | Schering Aktiengesellschaft | Treatment of climacteric disorders with nitric oxide synthase substrates and/or donors |
EP0675732B1 (en) * | 1993-07-27 | 2006-06-28 | Mario Bigazzi | Use of relaxin in the manufacture of therapeutic agents |
US5631373A (en) * | 1993-11-05 | 1997-05-20 | State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education, Acting For And On Behalf Of The Oregon Health Sciences University And The University Of Oregon, Eugene Oregon | Alkyl, azido, alkoxy, and fluoro-substituted and fused quinoxalinediones |
US5470847A (en) * | 1993-12-10 | 1995-11-28 | Board Of Regents, The University Of Texas System | Ovulation control by regulating nitric oxide levels with arginine derivatives |
US5441946A (en) * | 1994-04-14 | 1995-08-15 | Rhone-Poulenc-Rorer Pharmaceuticals, Inc. | Phosphonate derivatives of lipophilic amines |
US5811416A (en) * | 1994-06-06 | 1998-09-22 | Board Of Regents The University Of Texas System | Endothelin antagonist and/or endothelin synthase inhibitor in combination with a progestin, an estrogen, a cyclooxygenase inhibitor, or a nitric acid donor or substrate |
US6239172B1 (en) * | 1997-04-10 | 2001-05-29 | Nitrosystems, Inc. | Formulations for treating disease and methods of using same |
US6425881B1 (en) * | 1994-10-05 | 2002-07-30 | Nitrosystems, Inc. | Therapeutic mixture useful in inhibiting lesion formation after vascular injury |
US5543430A (en) * | 1994-10-05 | 1996-08-06 | Kaesemeyer; W. H. | Method and formulation of stimulating nitric oxide synthesis |
US5968983A (en) * | 1994-10-05 | 1999-10-19 | Nitrosystems, Inc | Method and formulation for treating vascular disease |
US5648101A (en) * | 1994-11-14 | 1997-07-15 | Tawashi; Rashad | Drug delivery of nitric oxide |
US5681819A (en) * | 1994-12-01 | 1997-10-28 | Oklahoma Medical Research Foundation | Method and compositions for reducing cholesterol absorption |
JP3598389B2 (ja) * | 1995-01-24 | 2004-12-08 | 大塚製薬株式会社 | 粉末清涼飲料製剤の安定保存法及び粉末清涼飲料製剤 |
US5900433A (en) * | 1995-06-23 | 1999-05-04 | Cormedics Corp. | Vascular treatment method and apparatus |
IT1277898B1 (it) * | 1995-08-03 | 1997-11-12 | Mendes Srl | Uso di amminoacidi basici, di acil derivati di amminoacidi basici e di loro sali farmaceuticamente accettabili per la profilassi di malattie |
EP0765660A3 (en) * | 1995-09-28 | 1998-09-23 | Takeda Chemical Industries, Ltd. | Microcapsules comprising 2-piperazinone-1-acetic acid compounds |
SE9600070D0 (sv) * | 1996-01-08 | 1996-01-08 | Astra Ab | New oral pharmaceutical dosage forms |
US5789442A (en) * | 1996-01-18 | 1998-08-04 | Schering Aktiengesellschaft | Treatment of urinary incontinence with nitric oxide synthase substrates and/or nitric oxide donors alone or in combination with estrogen or progesterone and/or other agents |
US6127421A (en) * | 1996-01-31 | 2000-10-03 | The Board Of Trustees Of The University Of Arkansas | In ovo use of L-arginine and salts thereof in the prevention and/or treatment of pulmonary hypertension syndrome in avians |
US5895788A (en) * | 1996-01-31 | 1999-04-20 | The Board Of Trustees Of The University Of Arkansas | Use of L-arginine and salts thereof in drinking water for the prevention and/or treatment of pulmonary hypertension syndrome in avians |
US6323211B1 (en) * | 1996-02-02 | 2001-11-27 | Nitromed, Inc. | Compositions and methods for treating sexual dysfunctions |
US5898038A (en) * | 1996-03-19 | 1999-04-27 | Board Of Regents, The University Of Texas System | Treatment of osteoporosis and metabolic bone disorders with nitric oxide substrate and/or donors |
US5910482A (en) * | 1996-03-19 | 1999-06-08 | Board Of Regents, The University Of Texas System | Treatment or prevention of preeclampsia, eclampsia with calcitonin gene related peptide, CGRP analog, progestational agent, nitric oxide source, and cyclooxygenase inhibitor |
US6040340A (en) * | 1996-05-07 | 2000-03-21 | Schering Aktiengesellschaft | Implantation rates after in vitro fertilization, treatment of infertility and early pregnancy loss with a nitric oxide donor alone or in combination with progesterone, and a method for contraception with nitric oxide inhibitors |
US5789422A (en) * | 1996-10-28 | 1998-08-04 | Schering Corporation | Substituted arylalkylamines as neurokinin antagonists |
US6210700B1 (en) * | 1997-01-14 | 2001-04-03 | Novartis Nutrition Ag | Enhancement of transplant graft survival through nutritional immunomodulation with omega-9 fatty acid dietary supplement therapy |
US5788987A (en) * | 1997-01-29 | 1998-08-04 | Poli Industria Chimica Spa | Methods for treating early morning pathologies |
US5912019A (en) * | 1997-02-07 | 1999-06-15 | Musc Foundation For Research Development | Compounds for reducing ischemia/reperfusion injury |
US6028107A (en) * | 1997-02-27 | 2000-02-22 | Waugh; William Howard | Orthomolecular medical use of L-citrulline for vasoprotection, relaxative smooth muscle tone and cell protection |
US5906987A (en) * | 1997-03-10 | 1999-05-25 | Schering Aktiengesellschaft And Board Of Regents | Treatment of male climacteric disorders with nitric oxide synthase substrates and/or donors, in combination with androgens and/or aromatase inhibitors |
US6312724B1 (en) * | 1997-04-04 | 2001-11-06 | Isa Odidi | Sustained release pharmaceutical matrix tablet of pharmaceutically acceptable salts of diclofenac and process for preparation thereof |
US20030114515A1 (en) * | 1997-04-10 | 2003-06-19 | Kaesemeyer Wayne H. | Therapeutic mixture of HMG-COA reductase inhibitors |
US5922332A (en) * | 1997-09-17 | 1999-07-13 | Fossel; Eric T. | Topical delivery of arginine to overcome pain |
US6207713B1 (en) * | 1997-09-17 | 2001-03-27 | Eric T. Fossel | Topical and oral delivery of arginine to cause beneficial effects |
US5895658A (en) * | 1997-09-17 | 1999-04-20 | Fossel; Eric T. | Topical delivery of L-arginine to cause tissue warming |
US6004925A (en) * | 1997-09-29 | 1999-12-21 | J. L. Dasseux | Apolipoprotein A-I agonists and their use to treat dyslipidemic disorders |
US6147109A (en) * | 1997-10-14 | 2000-11-14 | The General Hospital Corporation | Upregulation of Type III endothelial cell Nitric Oxide Synthase by HMG-CoA reductase inhibitors |
US20050038102A1 (en) * | 1997-10-14 | 2005-02-17 | Brigham And Womens Hospital | Upregulation of type III endothelial cell Nitric Oxide Synthase by HMG-CoA reductase inhibitors |
CA2306096A1 (en) * | 1997-10-15 | 1999-04-22 | Thomas Jefferson University | Nitric oxide donor compositions, methods, apparatus, and kits for preventing or alleviating vasoconstriction or vasospasm in a mammal |
GB2364304B (en) * | 1997-10-27 | 2003-04-23 | Reddy Research Foundation | Novel tricyclic compounds and their use in medicine process for their preparation and pharmaceutical compositions containing them |
US6174548B1 (en) * | 1998-08-28 | 2001-01-16 | Andrx Pharmaceuticals, Inc. | Omeprazole formulation |
US6558699B2 (en) * | 1997-11-17 | 2003-05-06 | Smithkline Beecham Corporation | High drug load immediate and modified release oral dosage formulations and processes for their manufacture |
WO1999026657A1 (en) * | 1997-11-25 | 1999-06-03 | Musc Foundation For Research Development | Inhibitors of nitric oxide synthase |
ATE277038T1 (de) * | 1997-12-23 | 2004-10-15 | Amersham Health As | Stickstoffoxid freisetzende chelatbildner und ihre therapeutische verwendung |
US6180597B1 (en) * | 1998-03-19 | 2001-01-30 | Brigham And Women's Hospital, Inc. | Upregulation of Type III endothelial cell nitric oxide synthase by rho GTPase function inhibitors |
US6063432A (en) * | 1998-05-19 | 2000-05-16 | Cooke Pharma | Arginine or lysine containing fruit healthbar formulation |
US6117872A (en) * | 1998-06-23 | 2000-09-12 | The Board Of Trustees Of The Leland Stanford Junior University | Enhancement of exercise performance by augmenting endogenous nitric oxide production or activity |
US6423751B1 (en) * | 1998-07-14 | 2002-07-23 | The Brigham And Women's Hospital, Inc. | Upregulation of type III endothelial cell nitric oxide synthase by agents that disrupt actin cytoskeletal organization |
US6207190B1 (en) * | 1998-08-13 | 2001-03-27 | Chronorx, Llc | Dosage forms for the treatment of the chronic glaucomas |
JP2002539257A (ja) * | 1999-03-19 | 2002-11-19 | イーノス・ファーマシューティカルス・インコーポレーテッド | 薬剤の脳内生物学的利用率の増加 |
US6359007B1 (en) * | 1999-04-07 | 2002-03-19 | Chronorx, Llc | Clinical uses for L-arginine ascorbate and various metalloarginate complexes |
US6419954B1 (en) * | 2000-05-19 | 2002-07-16 | Yamanouchi Pharmaceutical Co., Ltd. | Tablets and methods for modified release of hydrophilic and other active agents |
US6475530B1 (en) * | 2000-05-31 | 2002-11-05 | Eric H. Kuhrts | Methods and compositions for producing weight loss |
SI1292293T1 (en) * | 2000-06-09 | 2004-06-30 | LEK farmacevtska dru�ba d.d. | Stabilized pharmaceutically effective composition and pharmaceutical formulation comprising the same |
UA77660C2 (en) * | 2000-10-03 | 2007-01-15 | Compositions and methods for reducing plasma lipoprotein a level in human | |
US6696094B2 (en) * | 2000-10-18 | 2004-02-24 | Tzu-Sheng Wu | Herbal pharmaceutical composition for treatment of HIV/AIDS patients |
US6689385B2 (en) * | 2000-11-03 | 2004-02-10 | Chronorx Llc | Formulations for the treatment of insulin resistance and type 2 diabetes mellitus |
US6693094B2 (en) * | 2001-03-22 | 2004-02-17 | Chrono Rx Llc | Biguanide and sulfonylurea formulations for the prevention and treatment of insulin resistance and type 2 diabetes mellitus |
US20060029668A1 (en) * | 2002-10-24 | 2006-02-09 | Ron Eyal S | Sustained release L-arginine formulations and methods of manufacture and use |
US6797705B2 (en) * | 2002-12-16 | 2004-09-28 | Endomatrix, Inc. | Rhamnan sulphate composition for treatment of endothelial dysfunction |
US20040208893A1 (en) * | 2002-12-16 | 2004-10-21 | Daniels Bruce Alan | Seaweed extract composition for treatment of diabetes and diabetic complications |
US20040180077A1 (en) * | 2003-03-05 | 2004-09-16 | Riker Donald K. | Rapidly dissolving edible strips for treating obesity |
-
2003
- 2003-10-24 KR KR1020057007175A patent/KR20050083827A/ko not_active Application Discontinuation
- 2003-10-24 EP EP03779284A patent/EP1562555A2/en not_active Withdrawn
- 2003-10-24 JP JP2005501690A patent/JP2006514100A/ja not_active Withdrawn
- 2003-10-24 CA CA002503284A patent/CA2503284A1/en not_active Abandoned
- 2003-10-24 WO PCT/US2003/033931 patent/WO2004037203A2/en active Application Filing
- 2003-10-24 NZ NZ539672A patent/NZ539672A/en unknown
- 2003-10-24 AU AU2003284962A patent/AU2003284962B2/en not_active Expired - Fee Related
- 2003-10-24 MX MXPA05004290A patent/MXPA05004290A/es unknown
-
2005
- 2005-01-24 US US11/042,599 patent/US20050287210A1/en not_active Abandoned
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2015533134A (ja) * | 2012-10-09 | 2015-11-19 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 錠剤の機械的安定性に適切な少なくとも1種の水和物形成活性物質及び/又はアジュバントを含有する機械的に安定な錠剤、特にアルギニン含有錠剤の製造における選択的に水分調整された打錠材料の使用 |
Also Published As
Publication number | Publication date |
---|---|
KR20050083827A (ko) | 2005-08-26 |
AU2003284962B2 (en) | 2009-04-02 |
MXPA05004290A (es) | 2005-11-23 |
WO2004037203A3 (en) | 2004-09-16 |
AU2003284962A1 (en) | 2004-05-13 |
CA2503284A1 (en) | 2004-05-06 |
US20050287210A1 (en) | 2005-12-29 |
WO2004037203A2 (en) | 2004-05-06 |
EP1562555A2 (en) | 2005-08-17 |
WO2004037203A9 (en) | 2004-07-22 |
NZ539672A (en) | 2006-09-29 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20050287210A1 (en) | Sustained release L-arginine formulations and methods of manufacture and use | |
US20060029668A1 (en) | Sustained release L-arginine formulations and methods of manufacture and use | |
JP4870869B2 (ja) | HMG−CoA還元酵素阻害剤とニコチン酸化合物との組み合わせ、及び夜に1日1回高脂質血症を治療する方法 | |
US20050288372A1 (en) | Methods of treating various conditions by administration of sustained released L-Arginine | |
US20050288373A1 (en) | Methods of treating various conditions by administration of sustained release L-arginine | |
US20050147670A1 (en) | Oral disintegrating dosage forms | |
EP2921170A1 (en) | Combination immediate release controlled release levodopa/carbidopa dosage forms | |
RU2670272C2 (ru) | Пероральная фармацевтическая композиция, подходящая для повышения эффективности лечения двигательных нарушений | |
WO2003094909A2 (en) | Methods and compositions for the treatment and prevention of intermittent claudication or alzheimer's disease | |
JP2010505943A (ja) | 時間治療理論に基づく循環器疾患の治療用組合せ製剤 | |
KR20060085686A (ko) | 피브레이트를 포함하는 고형 제제 | |
AU2003247409B2 (en) | Combination immediate release controlled release levodopa/carbidopa dosage forms | |
WO2007016679A2 (en) | Combination immediate release controlled release levodopa and carbidopa dosage forms | |
US20030147957A1 (en) | Dual release formulation comprising levodopa ethyl ester and a decarboxylase inhibitor in immediate release layer with levodopa ethyl ester and a decarboxylase inhibitor in a controlled release core | |
US20080145424A1 (en) | Sustained release L-arginine formulations and methods of manufacture and use | |
JP2008538740A (ja) | 徐放性l−アルギニンの投与による各種症状の治療方法 | |
AU2006208293A1 (en) | Methods of treating various conditions by administration of sustained release L-arginine | |
CN1731985A (zh) | 缓释l-精氨酸制剂及其生产和使用方法 | |
HUE029193T2 (en) | Delayed release drug formulations of thiocolchicoside |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20061024 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20061024 |
|
A711 | Notification of change in applicant |
Free format text: JAPANESE INTERMEDIATE CODE: A711 Effective date: 20080201 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20080201 |
|
A761 | Written withdrawal of application |
Free format text: JAPANESE INTERMEDIATE CODE: A761 Effective date: 20100420 |