CN115671064A - 全天然无毒舌下药物递送系统 - Google Patents
全天然无毒舌下药物递送系统 Download PDFInfo
- Publication number
- CN115671064A CN115671064A CN202211170568.9A CN202211170568A CN115671064A CN 115671064 A CN115671064 A CN 115671064A CN 202211170568 A CN202211170568 A CN 202211170568A CN 115671064 A CN115671064 A CN 115671064A
- Authority
- CN
- China
- Prior art keywords
- tablet
- delivery vehicle
- sublingual
- sildenafil
- active agent
- 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.)
- Pending
Links
- 231100000252 nontoxic Toxicity 0.000 title abstract description 4
- 230000003000 nontoxic effect Effects 0.000 title abstract description 4
- 238000012377 drug delivery Methods 0.000 title description 2
- 239000000203 mixture Substances 0.000 claims abstract description 22
- 239000013543 active substance Substances 0.000 claims abstract description 20
- BNRNXUUZRGQAQC-UHFFFAOYSA-N sildenafil Chemical compound CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 BNRNXUUZRGQAQC-UHFFFAOYSA-N 0.000 claims description 47
- 238000000034 method Methods 0.000 claims description 28
- 229960003310 sildenafil Drugs 0.000 claims description 21
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 18
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 claims description 15
- 239000000843 powder Substances 0.000 claims description 13
- DEIYFTQMQPDXOT-UHFFFAOYSA-N sildenafil citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 DEIYFTQMQPDXOT-UHFFFAOYSA-N 0.000 claims description 10
- 229960002639 sildenafil citrate Drugs 0.000 claims description 10
- 238000004090 dissolution Methods 0.000 claims description 9
- 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 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 8
- 102000004877 Insulin Human genes 0.000 claims description 7
- 108090001061 Insulin Proteins 0.000 claims description 7
- 239000000796 flavoring agent Substances 0.000 claims description 7
- 229940125396 insulin Drugs 0.000 claims description 7
- 102000003951 Erythropoietin Human genes 0.000 claims description 6
- 108090000394 Erythropoietin Proteins 0.000 claims description 6
- 102000004457 Granulocyte-Macrophage Colony-Stimulating Factor Human genes 0.000 claims description 6
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 claims description 6
- 102000002265 Human Growth Hormone Human genes 0.000 claims description 6
- 108010000521 Human Growth Hormone Proteins 0.000 claims description 6
- 239000000854 Human Growth Hormone Substances 0.000 claims description 6
- 102000007651 Macrophage Colony-Stimulating Factor Human genes 0.000 claims description 6
- 108010046938 Macrophage Colony-Stimulating Factor Proteins 0.000 claims description 6
- 102000003982 Parathyroid hormone Human genes 0.000 claims description 6
- 108090000445 Parathyroid hormone Proteins 0.000 claims description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- 229940105423 erythropoietin Drugs 0.000 claims description 6
- 239000000199 parathyroid hormone Substances 0.000 claims description 6
- 229960001319 parathyroid hormone Drugs 0.000 claims description 6
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 claims description 6
- SNIOPGDIGTZGOP-UHFFFAOYSA-N Nitroglycerin Chemical compound [O-][N+](=O)OCC(O[N+]([O-])=O)CO[N+]([O-])=O SNIOPGDIGTZGOP-UHFFFAOYSA-N 0.000 claims description 5
- 239000000006 Nitroglycerin Substances 0.000 claims description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 5
- 229960003711 glyceryl trinitrate Drugs 0.000 claims description 5
- 210000003296 saliva Anatomy 0.000 claims description 5
- IYFNEFQTYQPVOC-UHFFFAOYSA-N udenafil Chemical compound C1=C(C=2NC=3C(CCC)=NN(C)C=3C(=O)N=2)C(OCCC)=CC=C1S(=O)(=O)NCCC1CCCN1C IYFNEFQTYQPVOC-UHFFFAOYSA-N 0.000 claims description 5
- MJEXYQIZUOHDGY-UHFFFAOYSA-N Homosildenafil Chemical compound CCCC1=NN(C)C(C(N=2)=O)=C1NC=2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(CC)CC1 MJEXYQIZUOHDGY-UHFFFAOYSA-N 0.000 claims description 4
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 4
- SECKRCOLJRRGGV-UHFFFAOYSA-N Vardenafil Chemical compound CCCC1=NC(C)=C(C(N=2)=O)N1NC=2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(CC)CC1 SECKRCOLJRRGGV-UHFFFAOYSA-N 0.000 claims description 4
- 229940049706 benzodiazepine Drugs 0.000 claims description 4
- 150000001557 benzodiazepines Chemical class 0.000 claims description 4
- 235000012000 cholesterol Nutrition 0.000 claims description 4
- 235000015165 citric acid Nutrition 0.000 claims description 4
- 235000013355 food flavoring agent Nutrition 0.000 claims description 4
- 239000012634 fragment Substances 0.000 claims description 4
- 235000019359 magnesium stearate Nutrition 0.000 claims description 4
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 4
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 4
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 4
- KQKPFRSPSRPDEB-UHFFFAOYSA-N sumatriptan Chemical compound CNS(=O)(=O)CC1=CC=C2NC=C(CCN(C)C)C2=C1 KQKPFRSPSRPDEB-UHFFFAOYSA-N 0.000 claims description 4
- 229960003708 sumatriptan Drugs 0.000 claims description 4
- 229960000438 udenafil Drugs 0.000 claims description 4
- 229960002381 vardenafil Drugs 0.000 claims description 4
- WJFKNYWRSNBZNX-UHFFFAOYSA-N 10H-phenothiazine Chemical compound C1=CC=C2NC3=CC=CC=C3SC2=C1 WJFKNYWRSNBZNX-UHFFFAOYSA-N 0.000 claims description 3
- NEYKRKVLEWKOBI-UHFFFAOYSA-N 5-[2-ethoxy-5-[4-(2-hydroxyethyl)piperazin-1-yl]sulfonylphenyl]-1-methyl-3-propyl-4h-pyrazolo[4,3-d]pyrimidin-7-one Chemical compound CCCC1=NN(C)C(C(N=2)=O)=C1NC=2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(CCO)CC1 NEYKRKVLEWKOBI-UHFFFAOYSA-N 0.000 claims description 3
- 102000055006 Calcitonin Human genes 0.000 claims description 3
- 108060001064 Calcitonin Proteins 0.000 claims description 3
- 101001081479 Homo sapiens Islet amyloid polypeptide Proteins 0.000 claims description 3
- 102000015696 Interleukins Human genes 0.000 claims description 3
- 108010063738 Interleukins Proteins 0.000 claims description 3
- 108010041872 Islet Amyloid Polypeptide Proteins 0.000 claims description 3
- 102000036770 Islet Amyloid Polypeptide Human genes 0.000 claims 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 claims description 3
- 229930006000 Sucrose Natural products 0.000 claims description 3
- 229940035674 anesthetics Drugs 0.000 claims description 3
- BBBFJLBPOGFECG-VJVYQDLKSA-N calcitonin Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(N)=O)C(C)C)C(=O)[C@@H]1CSSC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 BBBFJLBPOGFECG-VJVYQDLKSA-N 0.000 claims description 3
- 229960004015 calcitonin Drugs 0.000 claims description 3
- 235000019634 flavors Nutrition 0.000 claims description 3
- 239000003193 general anesthetic agent Substances 0.000 claims description 3
- 239000004615 ingredient Substances 0.000 claims description 3
- 229940047122 interleukins Drugs 0.000 claims description 3
- 230000000873 masking effect Effects 0.000 claims description 3
- 229950000688 phenothiazine Drugs 0.000 claims description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 3
- 239000005720 sucrose Substances 0.000 claims description 3
- 230000024883 vasodilation Effects 0.000 claims description 3
- 239000012896 selective serotonin reuptake inhibitor Substances 0.000 claims 4
- 229940124834 selective serotonin reuptake inhibitor Drugs 0.000 claims 4
- 229920002785 Croscarmellose sodium Polymers 0.000 claims 2
- 239000004376 Sucralose Substances 0.000 claims 2
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 claims 2
- 229960005168 croscarmellose Drugs 0.000 claims 2
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 claims 2
- 239000000377 silicon dioxide Substances 0.000 claims 2
- 235000012239 silicon dioxide Nutrition 0.000 claims 2
- 235000019408 sucralose Nutrition 0.000 claims 2
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 claims 2
- 235000004936 Bromus mango Nutrition 0.000 claims 1
- 240000007228 Mangifera indica Species 0.000 claims 1
- 235000014826 Mangifera indica Nutrition 0.000 claims 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims 1
- 235000009184 Spondias indica Nutrition 0.000 claims 1
- 239000008240 homogeneous mixture Substances 0.000 claims 1
- 150000002990 phenothiazines Chemical class 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 16
- 238000009472 formulation Methods 0.000 abstract description 14
- 238000010521 absorption reaction Methods 0.000 abstract description 5
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 21
- 239000003814 drug Substances 0.000 description 20
- 229940079593 drug Drugs 0.000 description 16
- 229960000672 rosuvastatin Drugs 0.000 description 13
- 239000003826 tablet Substances 0.000 description 12
- 239000000546 pharmaceutical excipient Substances 0.000 description 11
- 235000002639 sodium chloride Nutrition 0.000 description 11
- 239000002775 capsule Substances 0.000 description 10
- 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 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 150000003839 salts Chemical class 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 239000004480 active ingredient Substances 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 8
- 239000006190 sub-lingual tablet Substances 0.000 description 8
- 108010010803 Gelatin Proteins 0.000 description 7
- 230000009471 action Effects 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 7
- 239000002552 dosage form Substances 0.000 description 7
- 229920000159 gelatin Polymers 0.000 description 7
- 239000008273 gelatin Substances 0.000 description 7
- 235000019322 gelatine Nutrition 0.000 description 7
- 235000011852 gelatine desserts Nutrition 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- 229910052708 sodium Inorganic materials 0.000 description 7
- 235000000346 sugar Nutrition 0.000 description 7
- 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 description 6
- 230000008901 benefit Effects 0.000 description 6
- 239000000499 gel Substances 0.000 description 6
- 229920002643 polyglutamic acid Polymers 0.000 description 6
- 229960002855 simvastatin Drugs 0.000 description 6
- 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 description 6
- 239000002904 solvent Substances 0.000 description 6
- 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 5
- 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 5
- 239000002253 acid Substances 0.000 description 5
- 150000001412 amines Chemical group 0.000 description 5
- 239000012736 aqueous medium Substances 0.000 description 5
- 239000011324 bead Substances 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 238000001125 extrusion Methods 0.000 description 5
- 229960004844 lovastatin Drugs 0.000 description 5
- 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 5
- 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 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- -1 udenafil analog amine Chemical class 0.000 description 5
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 4
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 4
- 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 4
- 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 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 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 4
- 239000011575 calcium Substances 0.000 description 4
- 229910052791 calcium Inorganic materials 0.000 description 4
- 238000013270 controlled release Methods 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 239000003937 drug carrier Substances 0.000 description 4
- 229960002797 pitavastatin Drugs 0.000 description 4
- 230000003389 potentiating effect Effects 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 208000002815 pulmonary hypertension Diseases 0.000 description 4
- 239000000600 sorbitol Substances 0.000 description 4
- 235000010356 sorbitol Nutrition 0.000 description 4
- 150000008163 sugars Chemical class 0.000 description 4
- 239000011782 vitamin Substances 0.000 description 4
- 229940088594 vitamin Drugs 0.000 description 4
- 235000013343 vitamin Nutrition 0.000 description 4
- 229930003231 vitamin Natural products 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- ZGGHKIMDNBDHJB-NRFPMOEYSA-M (3R,5S)-fluvastatin sodium Chemical compound [Na+].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 ZGGHKIMDNBDHJB-NRFPMOEYSA-M 0.000 description 3
- 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 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-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
- 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 3
- 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 3
- 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 3
- 101100189582 Dictyostelium discoideum pdeD gene Proteins 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 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
- 101150098694 PDE5A gene Proteins 0.000 description 3
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 3
- 229920002125 Sokalan® Polymers 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 239000003945 anionic surfactant Substances 0.000 description 3
- 229960005370 atorvastatin Drugs 0.000 description 3
- 230000036772 blood pressure Effects 0.000 description 3
- 102100029175 cGMP-specific 3',5'-cyclic phosphodiesterase Human genes 0.000 description 3
- 229960005110 cerivastatin Drugs 0.000 description 3
- 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 3
- OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 description 3
- 238000007906 compression Methods 0.000 description 3
- 230000006835 compression Effects 0.000 description 3
- ZOOGRGPOEVQQDX-UHFFFAOYSA-N cyclic GMP Natural products O1C2COP(O)(=O)OC2C(O)C1N1C=NC2=C1NC(N)=NC2=O ZOOGRGPOEVQQDX-UHFFFAOYSA-N 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 239000008121 dextrose Substances 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 239000000945 filler Substances 0.000 description 3
- 229960003765 fluvastatin Drugs 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 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 3
- 229960002965 pravastatin Drugs 0.000 description 3
- 239000000661 sodium alginate Substances 0.000 description 3
- 229940005550 sodium alginate Drugs 0.000 description 3
- 159000000000 sodium salts Chemical class 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 230000000638 stimulation Effects 0.000 description 3
- 229940098466 sublingual tablet Drugs 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000004381 surface treatment Methods 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- DIWRORZWFLOCLC-HNNXBMFYSA-N (3s)-7-chloro-5-(2-chlorophenyl)-3-hydroxy-1,3-dihydro-1,4-benzodiazepin-2-one Chemical compound N([C@H](C(NC1=CC=C(Cl)C=C11)=O)O)=C1C1=CC=CC=C1Cl DIWRORZWFLOCLC-HNNXBMFYSA-N 0.000 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
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- 101100296726 Caenorhabditis elegans pde-5 gene Proteins 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 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
- 229920001353 Dextrin Polymers 0.000 description 2
- 239000004375 Dextrin Substances 0.000 description 2
- 101100135868 Dictyostelium discoideum pde3 gene Proteins 0.000 description 2
- 208000010228 Erectile Dysfunction Diseases 0.000 description 2
- PLDUPXSUYLZYBN-UHFFFAOYSA-N Fluphenazine Chemical compound C1CN(CCO)CCN1CCCN1C2=CC(C(F)(F)F)=CC=C2SC2=CC=CC=C21 PLDUPXSUYLZYBN-UHFFFAOYSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 108010065920 Insulin Lispro Proteins 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- 229920002774 Maltodextrin Polymers 0.000 description 2
- 239000005913 Maltodextrin Substances 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 229920000881 Modified starch Polymers 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 2
- BRUQQQPBMZOVGD-XFKAJCMBSA-N Oxycodone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C BRUQQQPBMZOVGD-XFKAJCMBSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- TUZYXOIXSAXUGO-UHFFFAOYSA-N Pravastatin Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(O)C=C21 TUZYXOIXSAXUGO-UHFFFAOYSA-N 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- ULUAUXLGCMPNKK-UHFFFAOYSA-N Sulfobutanedioic acid Chemical class OC(=O)CC(C(O)=O)S(O)(=O)=O ULUAUXLGCMPNKK-UHFFFAOYSA-N 0.000 description 2
- 102000011016 Type 5 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 description 2
- 108010037581 Type 5 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 description 2
- 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 2
- 150000007513 acids Chemical class 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 229960004538 alprazolam Drugs 0.000 description 2
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 2
- SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical compound [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 description 2
- 229960005070 ascorbic acid Drugs 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 2
- 159000000007 calcium salts Chemical class 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
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 230000000747 cardiac effect Effects 0.000 description 2
- 239000002738 chelating agent Substances 0.000 description 2
- 229960001403 clobazam Drugs 0.000 description 2
- CXOXHMZGEKVPMT-UHFFFAOYSA-N clobazam Chemical compound O=C1CC(=O)N(C)C2=CC=C(Cl)C=C2N1C1=CC=CC=C1 CXOXHMZGEKVPMT-UHFFFAOYSA-N 0.000 description 2
- DGBIGWXXNGSACT-UHFFFAOYSA-N clonazepam Chemical compound C12=CC([N+](=O)[O-])=CC=C2NC(=O)CN=C1C1=CC=CC=C1Cl DGBIGWXXNGSACT-UHFFFAOYSA-N 0.000 description 2
- 229960003120 clonazepam Drugs 0.000 description 2
- 229920001577 copolymer Polymers 0.000 description 2
- 210000005226 corpus cavernosum Anatomy 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 229940096516 dextrates Drugs 0.000 description 2
- 235000019425 dextrin Nutrition 0.000 description 2
- 229960003529 diazepam Drugs 0.000 description 2
- AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 2
- RBLGLDWTCZMLRW-UHFFFAOYSA-K dicalcium;phosphate;dihydrate Chemical compound O.O.[Ca+2].[Ca+2].[O-]P([O-])([O-])=O RBLGLDWTCZMLRW-UHFFFAOYSA-K 0.000 description 2
- XYYVYLMBEZUESM-UHFFFAOYSA-N dihydrocodeine Natural products C1C(N(CCC234)C)C2C=CC(=O)C3OC2=C4C1=CC=C2OC XYYVYLMBEZUESM-UHFFFAOYSA-N 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- GVGUFUZHNYFZLC-UHFFFAOYSA-N dodecyl benzenesulfonate;sodium Chemical compound [Na].CCCCCCCCCCCCOS(=O)(=O)C1=CC=CC=C1 GVGUFUZHNYFZLC-UHFFFAOYSA-N 0.000 description 2
- 229960002428 fentanyl Drugs 0.000 description 2
- IVLVTNPOHDFFCJ-UHFFFAOYSA-N fentanyl citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C=1C=CC=CC=1N(C(=O)CC)C(CC1)CCN1CCC1=CC=CC=C1 IVLVTNPOHDFFCJ-UHFFFAOYSA-N 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 239000010408 film Substances 0.000 description 2
- 238000010579 first pass effect Methods 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 229960002690 fluphenazine Drugs 0.000 description 2
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- FETSQPAGYOVAQU-UHFFFAOYSA-N glyceryl palmitostearate Chemical compound OCC(O)CO.CCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O FETSQPAGYOVAQU-UHFFFAOYSA-N 0.000 description 2
- 229940046813 glyceryl palmitostearate Drugs 0.000 description 2
- WNRQPCUGRUFHED-DETKDSODSA-N humalog Chemical compound C([C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CS)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@H](CO)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CS)NC(=O)[C@H](CS)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(O)=O)C1=CC=C(O)C=C1.C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CS)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CS)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 WNRQPCUGRUFHED-DETKDSODSA-N 0.000 description 2
- LLPOLZWFYMWNKH-CMKMFDCUSA-N hydrocodone Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)CC(=O)[C@@H]1OC1=C2C3=CC=C1OC LLPOLZWFYMWNKH-CMKMFDCUSA-N 0.000 description 2
- 229960000240 hydrocodone Drugs 0.000 description 2
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 201000001881 impotence Diseases 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 229960002068 insulin lispro Drugs 0.000 description 2
- 125000000686 lactone group Chemical group 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 229960004391 lorazepam Drugs 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 229940035034 maltodextrin Drugs 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 229920003145 methacrylic acid copolymer Polymers 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 229960003512 nicotinic acid Drugs 0.000 description 2
- 239000011664 nicotinic acid Substances 0.000 description 2
- 239000002736 nonionic surfactant Substances 0.000 description 2
- 229960004535 oxazepam Drugs 0.000 description 2
- ADIMAYPTOBDMTL-UHFFFAOYSA-N oxazepam Chemical compound C12=CC(Cl)=CC=C2NC(=O)C(O)N=C1C1=CC=CC=C1 ADIMAYPTOBDMTL-UHFFFAOYSA-N 0.000 description 2
- 229960002085 oxycodone Drugs 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 235000021317 phosphate Nutrition 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 229960003611 pramlintide Drugs 0.000 description 2
- 108010029667 pramlintide Proteins 0.000 description 2
- NRKVKVQDUCJPIZ-MKAGXXMWSA-N pramlintide acetate Chemical compound C([C@@H](C(=O)NCC(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CS)NC(=O)[C@@H](N)CCCCN)[C@@H](C)O)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 NRKVKVQDUCJPIZ-MKAGXXMWSA-N 0.000 description 2
- TUZYXOIXSAXUGO-PZAWKZKUSA-N pravastatin Chemical compound 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 TUZYXOIXSAXUGO-PZAWKZKUSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 230000001568 sexual effect Effects 0.000 description 2
- 235000010413 sodium alginate Nutrition 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 229940080264 sodium dodecylbenzenesulfonate Drugs 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 239000013589 supplement Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- LLPOLZWFYMWNKH-UHFFFAOYSA-N trans-dihydrocodeinone Natural products C1C(N(CCC234)C)C2CCC(=O)C3OC2=C4C1=CC=C2OC LLPOLZWFYMWNKH-UHFFFAOYSA-N 0.000 description 2
- 229960001727 tretinoin Drugs 0.000 description 2
- 229960003386 triazolam Drugs 0.000 description 2
- JOFWLTCLBGQGBO-UHFFFAOYSA-N triazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1Cl JOFWLTCLBGQGBO-UHFFFAOYSA-N 0.000 description 2
- JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 description 1
- IKAACYWAXDLDPM-UHFFFAOYSA-N 1,2,3,4,4a,5-hexahydronaphthalene Chemical group C1=CCC2CCCCC2=C1 IKAACYWAXDLDPM-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- OKMWKBLSFKFYGZ-UHFFFAOYSA-N 1-behenoylglycerol Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO OKMWKBLSFKFYGZ-UHFFFAOYSA-N 0.000 description 1
- RPOUGULCGNMIBX-UHFFFAOYSA-N 1-chlorophenazine Chemical compound C1=CC=C2N=C3C(Cl)=CC=CC3=NC2=C1 RPOUGULCGNMIBX-UHFFFAOYSA-N 0.000 description 1
- YQQSRZSUGBETRS-UHFFFAOYSA-N 1h-pyridazine-6-thione Chemical compound SC1=CC=CN=N1 YQQSRZSUGBETRS-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 229920002126 Acrylic acid copolymer Polymers 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical class [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 239000004382 Amylase Substances 0.000 description 1
- 102000013142 Amylases Human genes 0.000 description 1
- 108010065511 Amylases Proteins 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 108010075254 C-Peptide Proteins 0.000 description 1
- WDNDFFXELCXYOB-UHFFFAOYSA-L CCOS(OC(C(C(=O)[O-])S(=O)(=O)O)(C(=O)[O-])OS(=O)(=O)OCC)(=O)=O.[Na+].[Na+] Chemical compound CCOS(OC(C(C(=O)[O-])S(=O)(=O)O)(C(=O)[O-])OS(=O)(=O)OCC)(=O)=O.[Na+].[Na+] WDNDFFXELCXYOB-UHFFFAOYSA-L 0.000 description 1
- PTHCMJGKKRQCBF-UHFFFAOYSA-N Cellulose, microcrystalline Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC)C(CO)O1 PTHCMJGKKRQCBF-UHFFFAOYSA-N 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
- 101100351286 Dictyostelium discoideum pdeE gene Proteins 0.000 description 1
- 206010013654 Drug abuse Diseases 0.000 description 1
- 206010013710 Drug interaction 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
- 229920002907 Guar gum Polymers 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 1
- 108010044467 Isoenzymes Proteins 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 229940123333 Phosphodiesterase 5 inhibitor Drugs 0.000 description 1
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 1
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 1
- 229920002845 Poly(methacrylic acid) Polymers 0.000 description 1
- 108010020346 Polyglutamic Acid Proteins 0.000 description 1
- 206010052005 Psychogenic erectile dysfunction Diseases 0.000 description 1
- PPTYJKAXVCCBDU-UHFFFAOYSA-N Rohypnol Chemical compound N=1CC(=O)N(C)C2=CC=C([N+]([O-])=O)C=C2C=1C1=CC=CC=C1F PPTYJKAXVCCBDU-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- 201000001880 Sexual dysfunction Diseases 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- SEQDDYPDSLOBDC-UHFFFAOYSA-N Temazepam Chemical compound N=1C(O)C(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 SEQDDYPDSLOBDC-UHFFFAOYSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 208000003443 Unconsciousness Diseases 0.000 description 1
- 229920002494 Zein Polymers 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 210000000577 adipose tissue Anatomy 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 150000008055 alkyl aryl sulfonates Chemical class 0.000 description 1
- 150000008051 alkyl sulfates Chemical class 0.000 description 1
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 229920003144 amino alkyl methacrylate copolymer Polymers 0.000 description 1
- 239000002280 amphoteric surfactant Substances 0.000 description 1
- 235000019418 amylase Nutrition 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 235000019658 bitter taste Nutrition 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 1
- 239000006189 buccal tablet Substances 0.000 description 1
- 239000000337 buffer salt Substances 0.000 description 1
- 229960001948 caffeine Drugs 0.000 description 1
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- XAAHAAMILDNBPS-UHFFFAOYSA-L calcium hydrogenphosphate dihydrate Chemical compound O.O.[Ca+2].OP([O-])([O-])=O XAAHAAMILDNBPS-UHFFFAOYSA-L 0.000 description 1
- 239000001506 calcium phosphate Substances 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
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 229940078456 calcium stearate Drugs 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 239000003093 cationic surfactant Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 150000005829 chemical entities Chemical class 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229960004126 codeine Drugs 0.000 description 1
- 230000004456 color vision Effects 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 238000010924 continuous production Methods 0.000 description 1
- 238000013267 controlled drug release Methods 0.000 description 1
- 238000010411 cooking Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000007334 copolymerization reaction Methods 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- XLMALTXPSGQGBX-GCJKJVERSA-N dextropropoxyphene Chemical compound C([C@](OC(=O)CC)([C@H](C)CN(C)C)C=1C=CC=CC=1)C1=CC=CC=C1 XLMALTXPSGQGBX-GCJKJVERSA-N 0.000 description 1
- 229960004193 dextropropoxyphene Drugs 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 239000013583 drug formulation Substances 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 230000001856 erectile effect Effects 0.000 description 1
- 238000010931 ester hydrolysis Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 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
- 230000007717 exclusion Effects 0.000 description 1
- 229960002200 flunitrazepam Drugs 0.000 description 1
- 229960000304 folic acid Drugs 0.000 description 1
- 235000019152 folic acid Nutrition 0.000 description 1
- 239000011724 folic acid Substances 0.000 description 1
- 235000007983 food acid Nutrition 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- VZCCETWTMQHEPK-UHFFFAOYSA-N gamma-Linolensaeure Natural products CCCCCC=CCC=CCC=CCCCCC(O)=O VZCCETWTMQHEPK-UHFFFAOYSA-N 0.000 description 1
- VZCCETWTMQHEPK-QNEBEIHSSA-N gamma-linolenic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/CCCCC(O)=O VZCCETWTMQHEPK-QNEBEIHSSA-N 0.000 description 1
- 235000020664 gamma-linolenic acid Nutrition 0.000 description 1
- 229920000370 gamma-poly(glutamate) polymer Polymers 0.000 description 1
- 229960002733 gamolenic acid Drugs 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 229940049654 glyceryl behenate Drugs 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- LHGVFZTZFXWLCP-UHFFFAOYSA-N guaiacol Chemical class COC1=CC=CC=C1O LHGVFZTZFXWLCP-UHFFFAOYSA-N 0.000 description 1
- 235000010417 guar gum Nutrition 0.000 description 1
- 239000000665 guar gum Substances 0.000 description 1
- 229960002154 guar gum Drugs 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- DEIVNMVWRDMSMJ-UHFFFAOYSA-N hydrogen peroxide;oxotitanium Chemical compound OO.[Ti]=O DEIVNMVWRDMSMJ-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- GLUUGHFHXGJENI-UHFFFAOYSA-O hydron piperazine Chemical group [H+].C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-O 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 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 description 1
- 208000021822 hypotensive Diseases 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000002563 ionic surfactant Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229940039009 isoproterenol Drugs 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 150000002596 lactones Chemical group 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 229960001708 magnesium carbonate Drugs 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- 229960000869 magnesium oxide Drugs 0.000 description 1
- 229940057948 magnesium stearate Drugs 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- 238000007726 management method Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910000000 metal hydroxide Inorganic materials 0.000 description 1
- 150000004692 metal hydroxides Chemical class 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 229950009116 mevastatin Drugs 0.000 description 1
- 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 1
- 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 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 229960001454 nitrazepam Drugs 0.000 description 1
- KJONHKAYOJNZEC-UHFFFAOYSA-N nitrazepam Chemical compound C12=CC([N+](=O)[O-])=CC=C2NC(=O)CN=C1C1=CC=CC=C1 KJONHKAYOJNZEC-UHFFFAOYSA-N 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 239000002417 nutraceutical Substances 0.000 description 1
- 235000021436 nutraceutical agent Nutrition 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 229940082615 organic nitrates used in cardiac disease Drugs 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000006179 pH buffering agent Substances 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 229940055726 pantothenic acid Drugs 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- 101150037969 pde-6 gene Proteins 0.000 description 1
- JFCQEDHGNNZCLN-MABBKULESA-N pentanedioic acid Chemical group O[14C](=O)CCC[14C](O)=O JFCQEDHGNNZCLN-MABBKULESA-N 0.000 description 1
- 238000001050 pharmacotherapy Methods 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
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920000193 polymethacrylate Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229940068965 polysorbates Drugs 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 235000019814 powdered cellulose Nutrition 0.000 description 1
- 229920003124 powdered cellulose Polymers 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- GCYXWQUSHADNBF-AAEALURTSA-N preproglucagon 78-108 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 GCYXWQUSHADNBF-AAEALURTSA-N 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- OLBCVFGFOZPWHH-UHFFFAOYSA-N propofol Chemical compound CC(C)C1=CC=CC(C(C)C)=C1O OLBCVFGFOZPWHH-UHFFFAOYSA-N 0.000 description 1
- 229960004134 propofol Drugs 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 231100000628 reference dose Toxicity 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000004648 relaxation of smooth muscle Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 210000001525 retina Anatomy 0.000 description 1
- 229930002330 retinoic acid Natural products 0.000 description 1
- 231100000872 sexual dysfunction Toxicity 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 150000003384 small molecules Chemical class 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
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- RGEBGDYYHAFODH-DHMAKVBVSA-M sodium;(e,3r,5s)-7-[4-(4-fluorophenyl)-2-[methyl(methylsulfonyl)amino]-6-propan-2-ylpyrimidin-5-yl]-3,5-dihydroxyhept-6-enoate Chemical class [Na+].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 RGEBGDYYHAFODH-DHMAKVBVSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 229960004274 stearic acid Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 208000011117 substance-related disease Diseases 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 206010042772 syncope Diseases 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 235000019640 taste Nutrition 0.000 description 1
- 229960003188 temazepam Drugs 0.000 description 1
- OGBMKVWORPGQRR-UMXFMPSGSA-N teriparatide Chemical compound C([C@H](NC(=O)[C@H](CCSC)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@@H](N)CO)C(C)C)[C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CNC=N1 OGBMKVWORPGQRR-UMXFMPSGSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 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 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
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 239000004554 water soluble tablet Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000005019 zein Substances 0.000 description 1
- 229940093612 zein Drugs 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
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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
- A61J3/10—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of compressed tablets
-
- 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
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
-
- 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
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
-
- 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
-
- 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
-
- 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
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4816—Wall or shell material
- A61K9/4825—Proteins, e.g. gelatin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Physiology (AREA)
- Nutrition Science (AREA)
- Inorganic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Gynecology & Obstetrics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Reproductive Health (AREA)
- Endocrinology (AREA)
- Organic Chemistry (AREA)
- Zoology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- General Preparation And Processing Of Foods (AREA)
Abstract
全天然无毒舌下递送系统改进许多活性剂的吸收和起效概况,以及具有比针对部分化合物家族和传统专利调配物所预期的结果更好的生物可用性和药物动力学结果。
Description
相关申请的交叉参考
本申请主张2014年2月7日提交的美国临时申请第61/937,021号的全部巴黎公约(Paris Convention)权益和优先权,其内容通过此引用并入,如同其全文在本文中完全阐述一般。
背景技术
在所属领域中长期存在对活性剂复合以使其相应吸收和起效概况可以得到增强的需要。本发明涉及改进方法,其允许许多传统专利产品的,随着新复合的迫切需要之物和多种长期具有挑战性的部分更有效递送的问题最终得以解决。
在目前药学,基于补充剂和营养药剂市场的主要目标当中,其一是通过更安全并且更有效的手段来递送活性成分。为了执行这一目标,已经对采用例如定时释放机制进行研究,以及设计制造(engineer)药物动力学化合物以治疗哺乳动物,包括人类、宠物和测试个体。然而,本发明人已经采取选择的发明原理以实现并重新配置调配物以使得能够实现改进和增强的系统,以便促进某些活性成分的递送,从而可以减少给药方案和化学含量以改进安全性和功效。
在本发明的教导出现之前,舌下递送一直受到限制,并且对于治疗肺高血压、勃起功能障碍、胆固醇和血压问题的复合药剂的迫切与长期需要没有得到充分推进。
发明内容
简言之,如市场所需要的,新颖的增强型舌下递送系统改进许多活性剂的吸收和起效概况,以及具有比针对部分化合物家族和传统专利调配物所预期的结果更好的生物可用性和药物动力学结果。
根据实施例,提供多种有效向哺乳动物递送活性剂的压缩干粉舌下递送媒剂。这些媒剂尤其包括药剂、营养药剂、补充剂以及宠物产品。
根据实施例,提供一种新颖的增强型连续舌下胶囊挤出方法,其包含以下的组合:挤出至少一个偏心明胶胶囊壳;挤出至少一个明胶插塞组,填充挤出物;以及用相应明胶插塞插入所述胶囊壳;其中所述方法是连续的,胶囊直径由挤出模设定;胶囊长度通过最终切割步骤确定;并且最终所得胶囊的偏心性质提供薄壁以使得能够进行溶解或额外处理、其它作用机制中的至少一者。
根据实施例,提供一种新颖的增强型连续舌下胶囊挤出方法,其尤其递送血管扩张剂、胆固醇管理工具和用于治疗血压的药剂中的至少一者。
根据实施例,提供一种新颖的增强型连续舌下胶囊挤出方法,其有效用于递送比常规上认为有效的含量更低含量的活性成分。
根据实施例,提供一种连续偏移挤出式凝胶条的方法,其包含以下的组合:挤出至少一个偏移的明胶条;挤出至少成对的明胶插塞组;扩展填充物;以及对明胶盖挤出进行表面处理。
根据实施例,提供一种方法,所述方法是连续的,具有用挤出模设定的条尺寸;其中在某些方法结束时将所述条切割成所需长度;并且所述偏移条使薄壁溶解以使得能够改进活性成分向哺乳动物的递送。
附图说明
图1A到1D是根据本发明的各方面所选择的替代性压缩干粉舌下片剂形状。
图2A到2C图解说明所选择的与连续舌下胶囊扩展相关的实施例。
图3A到3C示意性地图解说明根据本发明教导的偏移凝胶条扩展处理器。
图4A和4B示意性地图解说明替代性表面处理方法。
图5A和5B描绘根据本发明的实施例,用于舌下井式凝胶条和凹陷式凝胶条的示意图和方法步骤。
图6A、6B和6C进一步图解说明根据本发明的实施例。
图7A和7B进一步图解说明根据本发明产生井式凝胶条的实施例和方法。
图8A和8B同样示意性地图解说明根据本发明的新颖增强型方法(process)和方法论(methodology)。
图9为描绘根据本发明教导的例示性实施例的表。
具体实施方式
本发明人已经调配并且测试了许多改进多种化合物群组和家族的吸收和起效功能的方法。作为本发明申请的优先权基础的临时申请中的附录包含由FDA和加利福尼亚州卫生部门(California Dept.of Health)授权的待由本发明人/被受让方制造、批发或重新包装的调配物列表。这些化学实体、化合物和家族中的许多已经得到描述,并且研究已经表明其舌下递送的未预期益处。因此,本发明人测试和调配较低剂量的所选择化合物并且实现出乎意料的较好结果,如本文所阐释和下文所要求保护的。
在最佳由舌下方法提供生物可用性改进的那些部分当中是例示性化合物以及用于肺高血压、血压、胆固醇问题和血管舒张的其它常见药剂。在不将所观察到的改进限制于一种作用机制的情况下,本发明人已经将研究扩展到介于以上所列到另一种磷酸二酯酶-5(PDE-5)抑制剂到用于糖尿病的药物治疗范围内的相关领域中。
通过此引用明确并入,如同其全文在本文中完全阐述一般的是以下专利和公开:US 5,260,440;US 6,316,460;US 6,002,021;US 4,444,784;US 5,159,104;US 6,100,407;EP 1 171 134;PCT/US2000/00662;US 8,497,370;US 7,279,457,US 3,428,728;US8,201,503;EP 1 019 039;US 2014/0011755;US 2013/0143894;US 2013/0059854;US2010/0209359;US 2010/0113453;US 2010/0069397;US 2007/0122355;US 2006/0099300;US 2003/0073133;US 2003/0022912;US 8,293,295;US 7,449,175;US 7,329,416;US 7,258,850;US 6,903,127;US 6,632,419;US 6,592,850;US 6,552,024;US 6,548,490;US6,531,114;US 6,428,769;US 6,403,597;US 6,342,251;US 6,211,156;US 6,200,591;WO2005/039530A1;WO 00/54777A1;EP 2,452,675A1;EP 1,536,769A2;EP 960,921A2;EP 1,171,134A1;DE 19834505A1;AU 3744800A;CN101683325A;CN10157930A;CN100488509C;CN101224222A;CN101057850A;US 8,563,534;US 8,501,715;US 8,481,570;US 8,211,922;US 8,158,611;US 7,279,459;US 7,186,704;GB 2497728A;CN 101991854A;US 8,012,503;US 7,163,705;CN 001600159A;US 2013/0123354;US 7,138,107;以及US 6,849,649。
先前可获得的受控释放舌下片剂调配物具有多种不足。本发明解决这些不足。如所描述的本发明尤其可适用于多种化合物,如以例如极低剂量的活性成分(例如西地那非)进行的工作所展示。副化合物(sub-compound)的使用对于本发明的实践是需要的,因为增加此药物的生物可用性有用于治疗肺高血压和精神性阳萎。此外,本发明允许成功使用较低浓度的此药物而不出现极其不良的严重副作用。
由体外研究已知,西地那非对于抑制5型磷酸二酯酶(PDE5)的选择性大致是对于其它已知磷酸二酯酶(例如PDE3)的4,000倍,所述PDE3涉及心脏收缩性的控制。据报导,与PDE6相比较,西地那非对PDE5的强效性仅是约10倍,所述PDE6是在视网膜中发现的酶,并且此较低选择性被认为是在较高剂量或血浆含量情况下观察到的与色觉相关的异常的基础。
一般来说,舌下剂型在至少约2分钟但小于约7分钟的时间段内溶解。本发明所涵盖的剂型在水中的溶解时间在约3分钟到约5分钟范围内。
包括活性剂(例如胰岛素)和一或多种在水性介质中快速溶解的赋形剂(例如螯合剂和/或增溶剂)的调配物同样被描述于本文中并且有本发明的教导涵盖。在所选择的实施例中,调配物适合于皮下或舌下给药。在皮下给予时,这些调配物通过粘膜表面(非经肠、肺等)并且通过脂肪组织快速吸收。这通过添加赋形剂,尤其增溶剂(例如酸和金属螯合剂)来实现。
如本文中一般所用,当最高剂量浓度在1-7.5的pH范围内可溶于250ml或更少的水性介质中时,将药物视为“高度可溶”。250ml的体积估计值来源于典型生物等效性(BE)研究方案,其规定用一杯(约8盎司)水向禁食人类志愿者给予药品。当基于质量测定或与静脉内参考剂量相比,90%或更多的给药剂量溶解时,将药物视为高度可溶的。溶解度可以通过摇瓶法或滴定法来测量、或通过指示有效稳定性的分析来分析。
如本文中一般所用,当使用美国药典(U.S.Pharmacopeia,USP)设备I在100rpm下(或设备II在50rpm下),不小于85%标记量的原料药在30分钟内溶解于900ml或更小体积的以下介质中的每一者:(1)0.1N HCl或不含酶的模拟胃液USP;(2)pH 4.5缓冲液;和(3)pH6.8缓冲液或不含酶的模拟肠液USP时,将立即释放药物调配物视为“快速溶解”。
尽管参考小分子药物(如胰岛素)进行描述,但本发明的调配物可以与其它药剂一起使用,所述药剂包括肽、蛋白质、核苷酸分子(RNA序列、DNA序列)、糖、多糖以及较小有机分子。在一些实例中,活性剂至少略微地可溶于水性介质中(即每份溶质10,000份水性溶剂),并且在其它实例中,活性剂在水性介质中为高度可溶。优选地,活性剂是高度强效的,以使得仅需要少量(例如在微克范围内)以提供治疗效果。合适的肽包括(但不限于)胰岛素和胰岛素衍生物,例如赖脯胰岛素(lispro);C肽;胰高血糖素样肽1(GLP1)和其所有活性片段;人类淀粉素和合成形式的淀粉素,例如普兰林肽(pramlintide);副甲状腺激素(parathyroid hormone,PTH)和其活性碎片(例如PTH1-34);降血钙素;人类生长激素(HGH);促红细胞生成素(EPO);巨噬细胞集落刺激因子(M-CSF);粒细胞-巨噬细胞集落刺激因子(GM-CSF);以及白介素。在优选实施例中,活性剂是胰岛素。合适的小分子包括硝化甘油、舒马曲坦(sumatriptan)、麻醉剂(例如芬太尼(fentanyl)、可待因(codeine)、丙氧芬(propoxyphene)、氢可酮(hydrocodone)和氧可酮(oxycodone))、苯二氮类(benzodiazepine)(例如阿普唑仑(Alprazolam)、氯巴占(Clobazam)、氯硝西泮(Clonazepam)、安定(Diazepam)、氟硝西泮(Flunitrazepam)、劳拉西泮(Lorazepam)、硝西泮(Nitrazepam)、奥沙西泮(Oxazepam)、替马西泮(Temazepam)和三唑仑(Triazolam))、吩噻嗪(phenothiazine)(氯丙嗪(Chlorpromazine)、氟非那嗪(Fluphenazine)、美索达嗪(Mesoridazine)、左美丙嗪(Methotrimeprazine)、哌氰嗪(Pericyazine)、佩吩嗪(Perphenazine)、丙氯拉嗪(Prochlorperazine)、硫丙拉嗪(Thioproperazine)、硫利达嗪(Thioridazine)、和三氟拉嗪(Trifluoperazine))以及选择性血清素再吸收抑制剂(selective serotonin reuptake inhibitor,SSRI)(例如舍曲林(sertraline)、氟伏沙明(fluvoxamine)、氟西汀(fluoxetine)、西它普兰(citalopram)和帕罗西汀(paroxetine))。
活性剂的剂量取决于其生物可用性和待治疗的病状、病痛(ailment)、疾病(disease)或病症。组合物任选地含有一或多种赋形剂。
在所选择的实施例中,与活性剂一起包括一或多种增溶剂以促进水性介质中的快速溶解。合适的增溶剂包括润湿剂,例如聚山梨醇酯和泊洛沙姆(poloxamer);非离子和离子型表面活性剂;食物酸和碱(例如碳酸氢钠);和醇;以及用于pH控制的缓冲盐。合适的酸包括乙酸、抗坏血酸、柠檬酸和盐酸。举例来说,如果活性剂是胰岛素,那么如所属领域的技术人员已知的,优选的增溶剂是柠檬酸。
稀释剂(在本文中也称为填充剂)通常是增加固体剂型的体积所必需的,以便为压制片剂或形成珠粒和颗粒提供切实可行的大小。合适的填充剂包括(但不限于)磷酸二钙二水合物、硫酸钙、乳糖、蔗糖、甘露糖醇、山梨糖醇、纤维素、微晶纤维素、粉末状纤维素、高岭土、氯化钠、无水淀粉、水解淀粉、预胶凝化淀粉、二氧化硅酮、三氧化钛、硅酸镁铝、碳酸钙、可压缩糖、糖球、粉末状糖(糖粉)、葡萄糖结合剂(dextrate)、糊精、右旋糖(dextrose)、脱水磷酸氢钙、棕榈基硬脂酸甘油酯、碳酸镁、氧化镁、麦芽糊精、聚甲基丙烯酸酯、氯化钾、滑石以及磷酸三钙。
粘合剂用于赋予固体剂量调配物内聚性质,并且因此确保片剂或珠粒或颗粒在剂型形成之后保持完整。合适的粘合剂材料包括(但不限于)淀粉、预胶凝化淀粉、明胶、糖(包括蔗糖、葡萄糖(glucose)、右旋糖(dextrose)、乳糖和山梨糖醇)、糊精、麦芽糊精、玉米蛋白、聚乙二醇、蜡、天然和合成胶(例如阿拉伯胶、瓜尔豆胶、黄蓍胶)、海藻酸盐、海藻酸钠、纤维素(包括羟丙基甲基纤维素、羧甲基纤维素钠、羟基丙基纤维素、羟乙基纤维素、乙基纤维素、甲基纤维素)和维格姆(veegum)、I型氢化植物油、硅酸镁铝、以及合成聚合物(例如丙烯酸和甲基丙烯酸共聚物、卡波姆(carbomer)、甲基丙烯酸共聚物、甲基丙烯酸甲酯共聚物、甲基丙烯酸氨基烷酯共聚物、聚丙烯酸/聚甲基丙烯酸和聚乙烯吡咯烷酮)。
润滑剂用于促进片剂制造。合适的润滑剂的实例包括(但不限于)硬脂酸镁、硬脂酸钙、硬脂酸、二十二酸甘油酯、单硬脂酸甘油酯、棕榈基硬脂酸甘油酯、氢化蓖麻油、I型氢化植物油、苯甲酸钠、月桂基硫酸钠、硬脂酰反丁烯二酸钠、聚乙二醇、滑石、硬脂酸锌以及矿物油和轻矿物油。
稳定剂用于抑制或延迟药物分解反应,其包括例如氧化反应。可以使用多种稳定剂。
表面活性剂可以是阴离子型、阳离子型、两性或非离子型表面活性剂。适合的阴离子型表面活性剂包括(但不限于)含有羧酸根、磺酸根以及硫酸根离子的那些表面活性剂。阴离子型表面活性剂的实例包括钠、钾、铵的长链烷基磺酸盐和烷基芳基磺酸盐,例如十二烷基苯磺酸钠;二烷基磺基琥珀酸钠,例如十二烷基苯磺酸钠;二烷基磺基琥珀酸钠,例如双-(2-乙基硫氧基)-磺基琥珀酸钠;以及烷基硫酸盐,例如月桂基硫酸钠。
如果需要,片剂、粉片、膜、口含片、珠粒、颗粒或粒子也可以含有次要量的无毒性辅助物质,例如染料、掩蔽剂、甜味剂、着色和调味剂、pH缓冲剂或防腐剂。
足以提供一定量的亲水特性的掺合或共聚合可以适用于改进材料的可湿性。活性化合物(或其药学上可接受的盐)可以按药物组合物形式给予,其中所述活性化合物呈与一或多种药学上可接受的载剂、赋形剂或稀释剂一起的混杂物或混合物形式。合适的剂型包括散剂、膜、粉片、口含片、胶囊以及片剂。在给药之后,剂型快速溶解,并且释放药物或形成含有药物,任选地含有一或多种赋形剂的较小粒子。
所选择的本发明调配物的变化形式可以在介于1秒到至少约3分钟、3到5分钟、5到8分钟或8到12分钟范围内的时间段中溶解。一种调配物的溶解时间小于30秒。根据本发明的教导,药物被快速吸收并输送到血浆中,产生快速作用起始(例如在给药之后约5分钟内开始并且在给药之后约15-30分钟时达到峰值)。
图9展示针对CITRIREXTM商标化合物(所选择的仅用于出口的调配物,科学实验室制药公司(SciLabs Pharmaceuticals),欧文(Irvine),CA 92614,FDA药物标签编码54317)改进的调配物。本发明人已经能够使用图1-8B中所图解说明的方法来逐步降低剂量需求以及克服苦味/味觉问题。
借助于本发明的教导在应用于治疗肺高血压时的益处的另一实例,极低剂量的化合物(如西地那非)可以是有效的,具有较低风险概况,并且在用全天然媒剂和系统递送时可以具有其它和另外的优点。
已知口服药品在性功能障碍上是尤其需要和寻求的考虑周到的治疗形式。最近,美国食品和药物管理局(FDA)已经批准经口使用西地那非的柠檬酸盐用于治疗男性勃起功能障碍。据报导,西地那非是环状GMP特异性5型磷酸二酯酶(PDE5)的选择性抑制剂,所述PDE5是形成于海绵体中的代谢环状GMP的主要同工酶。因为西地那非是海绵体中PDE5的强效抑制剂,其被认为可增强氧化氮释放。由于目前推荐剂量(25-100mg)下的西地那非在不存在性刺激的情况下作用极小,所以认为西地那非恢复对性刺激的自然勃起响应,而不在不存在此类刺激的情况下造成勃起。环状GMP刺激光滑肌肉松弛的局部机制尚未得到阐明。
在剂量-响应研究中,据报导,增加西地那非的剂量(25到100mg)增加西地那非产生勃起的功效。然而,经口给予西地那非也伴随着剂量反应性的不良的副作用,包括更严重的副作用,例如晕厥(丧失意识)、异常勃起(勃起持续4小时或更多)和心脏风险增加(性交型冠心病)。应注意的是,这些副作用在一些情况下,可能由生理学诱因、有害的药物相互作用或增效、或由药物滥用而引起。确切地说,低血压危机可能由西地那非柠檬酸盐和有机硝酸酯的组合导致,并且在一些情况下造成死亡,因此禁止向同时使用任何形式的有机硝酸酯(例如硝化甘油)的患者给予西地那非柠檬酸盐。因此,需要并且希望在较低剂量下促进西地那非的生物可用性,同时使副作用减到最少的经口给药形式。
从本世纪初起,早期舌下片剂在文献中有据可查。以舌下途径给予药物的主要原因是提供强效药物的快速作用起始。另一个原因是避免肝脏的首过代谢(first passmetabolism)。
术语“受控释放”在应用于舌下片剂时限于最大约60分钟。传统舌下片剂通常设计为由水溶性糖(例如山梨糖醇、乳糖、甘露糖醇等)制成的水溶性片剂。在文献中,受控释放的舌下片剂是极少的。罗伊(Lowey)的美国专利第3,428,728号(1969)描述由烹调用阿拉伯胶和山梨糖醇(通过加热)直到部分干燥,接着添加柠檬酸、颜色和风味剂,接着冷却来制成的受控释放舌下片剂。随后向可倾注糊状物添加活性成分,例如硝化甘油、咖啡因、愈创木酚盐(guaiocolate)、淀粉酶或异丙肾上腺素,其浇注成片剂。然而,罗伊的发现无法应用于通过压缩来制造片剂。药物制剂的释放时间是药物有效性的关键。本发明的舌下片剂可以通过压缩方法来制备,并且与先前技术对比,提供受控的药物释放。
因此,鉴于本发明教导的递送系统,包括西地那非、豪莫西地那非(Homosildenafil)、羟基豪莫西地那非、脱甲基西地那非、乙酰地那非(Acetidenafil)、伐地那非(Vardenafil)以及乌地那非(Udenafil)的西地那非类似物受到关注。西地那非可以代表那七种化合物,可以与他汀类(Statin)衍生物、γ-多聚谷氨酸衍生物、维生素或CMC钠反应以形成西地那非类似物的单季胺复合盐和乌地那非类似物的胺复合盐。由此,西地那非类似物可以表示西地那非、豪莫西地那非、羟基豪莫西地那非、脱甲基西地那非、乙酰地那非、伐地那非以及乌地那非。所涉及的哌嗪或胺部分以及他汀类、γ-多聚谷氨酸衍生物、维生素或CMC钠可以表示根据本发明教导的内容而有效用于舌下递送的明显或潜在组合。
因此,可获得他汀类的内酯环、酯和受保护的衍生物以制备以上可根据本发明教导递送的西地那非类似物单季胺复合盐或乌地那非类似物胺复合盐。
同样,他汀类衍生物和γ-多聚谷氨酸衍生物、维生素或CMC钠单独地与西地那非类似物的哌嗪基或西地那非类似物的吡咯烷基反应以制备西地那非类似物单季铵复合盐或西地那非类似物胺复合盐。优选的他汀类衍生物选自阿托伐他汀(Atorvastatin)、洛伐他汀(Lovastatin)、匹伐他汀(Pitavastatin)、罗素他汀(Rosuvastatin)以及辛伐他汀(Simvastatin),γ-多聚谷氨酸衍生物选自海藻酸钠、γ-多聚谷氨酸、聚谷氨酸钠、和GLT(称为赖氨酸、谷氨酸盐和酪氨酸的共聚物)以及聚谷氨酸钙-海藻酸钠,维生素选自视黄酸、抗坏血酸、叶酸、γ-亚麻酸、烟碱酸以及泛酸。由此,获得西地那非-γ-多聚谷氨酸、西地那非-辛伐他汀酸、西地那非-普伐他汀酸、西地那非-洛伐他汀酸、西地那非-匹伐他汀、西地那非-罗素他汀、西地那非-L-精胺酸、西地那非-CMC、西地那非-美伐他汀酸、西地那非-罗素他汀酸、西地那非-洛伐他汀酸、乌地那非-CMC、乌地那非-烟碱酸以及乌地那非-L-视黄酸。
以上提及的术语赋形剂或“药学上可接受的载剂或赋形剂”和“生物可用的载剂或赋形剂”包括已知用于制备剂型的任何适当的化合物,例如溶剂、分散剂、包衣、抗细菌剂或抗真菌剂以及防腐剂或延迟吸收剂。通常,此类载体或赋形剂自身不具有治疗活性。通过组合本发明中所揭示的衍生物与药学上可接受的载剂或赋形剂而制备的每一种调配物在向动物或人类给予时将不造成不良作用、过敏或其它不适当作用。因此,本发明中所揭示的衍生物与药学上可接受的载剂或赋形剂组合在临床使用和人类中可适用。治疗效果可以通过用舌下给药使用本发明中剂型来实现。向各种疾病患者给予每天约0.1mg到10mg的活性成分。
目前可广泛商购的他汀类包括阿托伐他汀、西立伐他汀(Cerivastatin)、氟伐他汀(Fluvastatin)、洛伐他汀、美伐他汀、普伐他汀、罗素他汀以及辛伐他汀。可以包括在本发明教导内容的范围内的各种他汀类的化学名称包含:洛伐他汀(揭示于美国专利第4,231,938号中),并且可以使用辛伐他汀(揭示于美国专利第4,444,784号中)。普伐他汀(揭示于美国专利第4,346,227号中)以钠盐形式给药。也以钠盐形式给药的氟伐他汀(揭示于美国专利第4,739,073号中)和西立伐他汀(揭示于美国专利第5,006,530号和第5,177,080号中)完全是合成化合物,其在结构上不同于包括六氢萘环的真菌衍生物所属于的药物种类。
商业他汀钙盐的结构包括两分子他汀和一分子钙。所谓的半钙盐称为一分子他汀和一分子钙的组合。罗素他汀、其钙盐和其内酯形式揭示于美国专利第5,260,440号中,所述专利在回流下获得罗素他汀的甲酯接着用NaBH4还原。此外,随后在室温下用氢氧化钠的乙醇溶液使所述酯水解,接着去除乙醇并且添加乙醚,获得罗素他汀的钠盐。另外,揭示于美国专利第6,316,460号中的罗素他汀组合物包括罗素他汀的多价磷酸盐。根据本发明的方法,在氮气氛下将罗素他汀钠盐溶解于水中并且添加到西地那非中,接着沉淀并结晶,根据实施例形成西地那非-罗素他汀酸单季哌嗪鎓复合盐。
他汀类可以通过中间物来制备,在所述中间物中,二醇戊酸基(开环形式)中羟基中的一或两者或内酯基(闭环形式)的羟基经由可水解保护基保护,并且羧基经由酯衍生物保护。美国专利第5,260,440号揭示罗素他汀的制备。美国专利第6,002,021号和第4,444,784号揭示一种用于制备辛伐他汀的方法,其适时使用环状保护基(例如二噁烷环状硫酸酯、环状磷酸酯和亚硼酸酯(borylidene))来取代烷基或芳基。另外,WO 95/13283揭示硼酸作为保护基,美国专利第5,159,104号揭示由乙酸酐进行的酯化,并且美国专利第6,100,407号也揭示一些保护基。
如所论述,可能组合的药剂包括选自由以下组成的群组的他汀类:阿托伐他汀、洛伐他汀、匹伐他汀、罗素他汀以及辛伐他汀,并且那些药物的他汀结构由金属氢氧化物(例如钠、钾、钙和氨的氢氧化物)和适用于使他汀酯基水解的酸水解。
由西地那非HCl盐形成西地那非-他汀酸复合物容易地通过使西地那非HCl盐与相等摩尔的氢氧化钠在可水解他汀类或他汀酯和衍生物的存在下反应来获得。钠离子优先可以在西地那非HCl盐的HCl部分进行等摩尔中和内,并且所得NaCl溶解于水合醇溶液中。在水与C1-C4低级醇(即乙醇和异丙醇)的混合溶液中,他汀展示离子状态、游离状态或与其它未反应的他汀酯衍生物混合。通过跟踪每一种他汀衍生物由足够量的氢氧化钠水解的量,术语“足够量的哌嗪鎓基或吡咯烷基”是约相等摩尔的量。
现参考图1A、1B、1C和1D,提供压缩粉末舌下成形形态用于考虑。圆形凸面和圆形凹面片剂两者都是形状有利的形式,其分别造成舌头下的移动,较厚的实体减慢溶解(凸面的),以及使得汇集的唾液能够加速溶解并且少量吸力减少移动(凹面的)。
更具体地参考图1C和1D,更椭圆的口服凹面片剂提供汇集唾液、加速溶解的盘状结构。细长形状同样减少移动。弯曲的卵形凹面片剂经过大小调整以得到与圆形凸面片剂相同的粉末体积,但(图1D)在用户虚拟磨合方面由于细长形状而具有减少移动的进一步形态优点,同时具有与上文所论述相同的汇集唾液优点。
现参考图2A、2B和2C,传授偏心挤出式胶囊,其由如图中所描绘的连续方法制成。
同样,图3A、3B和3C展示如上文所论述和下文所主张的用于偏移挤出式凝胶条的方法。
图4A和4B表明包装的另一种表面处理替代方案,其中将干粉成分与明胶混合在一起并且一起挤出。
图5A、5B和6A到6C同样图解说明用于制造具有活性成分填充物的舌下井式凝胶条的方法。
图7到8和所有子部分同样描绘如所属领域的技术人员已知的根据本发明的舌下方法。
已经为有需要的那些人调配根据本发明方法调配的许多化合物,并且其它化合物可以同样基于本文所完善的方法来制成。
虽然已经关于目前认为最实际并且优选的实施例描述方法和设备,但应理解本发明不必限于所揭示的实施例。希望涵盖包括在权利要求书精神和范围内的各种修改和类似安排,所述权利要求书的范围应符合最广泛解释以包涵所有此类修改和类似结构。本发明包括以下权利要求书的任何和所有实施例。
还应理解,可以在不脱离本发明本质的情况下进行多种变化。此类变化也隐含地包括于说明书中。其仍处于本发明的范围内。应理解本发明打算得到独立并作为整个系统地并且以方法和设备两种模式涵盖本发明许多方面的专利。
此外,本发明和权利要求书的各种要素中的每一者也可以按多种方式实现。本发明应理解为包涵每一种此类变化,不论所述变化是任何设备实施例的一个实施例变化、一种方法或过程实施例、或甚至仅是这些中任何要素的变化。
确切地说,应理解因为本发明涉及本发明的要素,所以即使在仅有功能或结果相同的情况下,用于每一要素的词也可以由等效的设备术语或方法术语来表达。
此类等效、广泛或甚至更通用的术语应视为包涵在每一要素或作用的描述中。此类术语可以在需要时被取代,以使得本发明授权的隐含宽涵盖范围得到明确。
应理解所有作用可以表示为进行所述作用的手段或表示为造成所述作用的要素。
类似地,所揭示的每一种物理要素应理解为包涵揭示所述物理要素所促进的作用。
在本专利申请中所提及得任何专利、公开或其它参考文献以引用的方式并入本文中。另外,对于所用每一术语,应理解除非其在本申请中的利用与此类解释不一致,否则常见词典定义应理解为针对每一术语和所有定义、替代性术语以及同义语进行并入,例如在由工作人员认可的标准技术词典中的至少一者和兰登书屋(Random House)《韦氏全本词典(Webster's Unabridged Dictionary)》中所含有的,其最新版本以引用的方式并入本文中。
最后,在信息揭示陈述或与本申请一起提交的其它信息陈述中所列的所有参考文献随附在此并且以引用的方式并入本文中;然而,对于以上中的每一者,如果以引用的方式并入此类信息或陈述可能被视为与此发明/这些发明的专利权不一致,那么此类陈述明确地不被视为由申请人进行。
就此而言,应理解出于实际原因并且为了避免添加数以百计权利要求的可能性,申请人仅递交具有最初从属权利要求的权利要求书。
支持应理解为达到有关新实体法(new matter laws)所要求的程度,以便能够在一项独立权利要求或概念之下增加各种的从属权利要求或其它要素,作为任何其它独立权利要求或概念的从属权利要求或要素,上述法律包括(但不限于)美国专利法35 USC 132或其它此类法律。
在进行非实质替代的程度内,在申请人实际上不将任何权利要求撰写成字面上包涵任何特定实施例的程度内,在以其它方式可适用的程度内,不能理解为申请人在任何情况下都打算或实际上放弃此类涵盖,因为申请人不可能预见所有不测事件;期望本领域的技术人员撰写出字面上包涵此类替代性实施例的权利要求也是不合理的。
此外,根据传统权利要求的解释,本文中使用过渡短语“包含”以用于保持“可广泛解释的”权利要求。因此,除非上下文另有要求,否则应理解术语“包含(comprise)”或变化(例如“包含(comprises)”或“包含(comprising)”)打算暗示包括所陈述的要素或步骤或要素或步骤的群组,但不排除任何其它要素或步骤或要素或步骤的群组。
此类术语应以其最广泛形式来解释,以使申请人获得法律许可的最广泛涵盖范围。
Claims (10)
1.一种压缩干粉片剂,
天然风味剂;
蔗糖素;
药学上的活性剂;
碳酸氢钠;
柠檬酸;
掩蔽风味剂;
硬脂酸镁;
交联羧甲纤维素;以及,
微晶纤维素105;
其中
所述活性剂的量为在每片剂至少0.01到10mg所述活性剂的范围内,所述片剂提供单位剂量;
所述片剂在舌下给药后于1秒到至少约3分钟内溶解;
所述片剂是由成分的均匀混合物形成的均匀压缩干粉;
所述片剂是凹形片剂从而唾液在凹面聚集以加速溶解;以及
其中所述药学上的活性剂用于管理胆固醇问题或用于血管舒张,或选自人类淀粉素和合成形式的淀粉素、副甲状腺激素(PTH)和其活性碎片、胰岛素、降血钙素、人类生长激素(HGH)、促红细胞生成素(EPO)、巨噬细胞集落刺激因子(M-CSF)、粒细胞-巨噬细胞集落刺激因子(GM-CSF)、白介素、硝化甘油、舒马曲坦、麻醉剂、苯二氮类、吩噻嗪以及选择性血清素再吸收抑制剂(SSRI)。
2.根据权利要求1所述的片剂,其中所述药学上的活性剂用于血管舒张。
4.根据权利要求3所述的递送媒剂,其中所述西地那非柠檬酸盐的量为在每单位剂量至少0.1到5mg西地那非柠檬酸盐的范围内。
5.根据权利要求3所述的递送媒剂,其中所述西地那非柠檬酸盐的量为在每单位剂量至少0.01到10mg西地那非柠檬酸盐的范围内。
6.根据权利要求3至5中任一项权利要求所述的递送媒剂,其中所述递送媒剂在小于30秒内溶解。
7.根据权利要求1或2所述的片剂,其中所述药学上的活性剂选自人类淀粉素和合成形式的淀粉素、副甲状腺激素(PTH)和其活性碎片、胰岛素、降血钙素、人类生长激素(HGH)、促红细胞生成素(EPO)、巨噬细胞集落刺激因子(M-CSF)、粒细胞-巨噬细胞集落刺激因子(GM-CSF)以及白介素。
8.根据权利要求1或2所述的片剂,其中所述药学上的活性剂选自硝化甘油、舒马曲坦、麻醉剂、苯二氮类、吩噻嗪以及选择性血清素再吸收抑制剂(SSRI)。
9.根据权利要求3所述的递送媒剂,其中所述药学上的活性剂选自、西地那非、豪莫西地那非、羟基豪莫西地那非、脱甲基西地那非、乙酰地那非、伐地那非以及乌地那非。
10.一种用于制备根据权利要求3中任一项权利要求所述的舌下递送媒剂的方法,包括:
配制包含调味剂、碳酸氢钠、柠檬酸、硬脂酸镁、微晶纤维素、蔗糖素和柠檬酸西地那非的均匀粉末混合物;以及
压制所述均匀粉末混合物以形成舌下递送媒剂,由此产生的所述舌下递送媒剂在舌下给药后在小于30秒内溶解。
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201461937021P | 2014-02-07 | 2014-02-07 | |
US61/937,021 | 2014-02-07 | ||
CN201480006550.2A CN105007904A (zh) | 2014-02-07 | 2014-03-07 | 全天然无毒舌下药物递送系统 |
PCT/US2014/022054 WO2015119641A1 (en) | 2014-02-07 | 2014-03-07 | All natural, non-toxic sublingual drug delivery systems |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201480006550.2A Division CN105007904A (zh) | 2014-02-07 | 2014-03-07 | 全天然无毒舌下药物递送系统 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN115671064A true CN115671064A (zh) | 2023-02-03 |
Family
ID=53333537
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202211170568.9A Pending CN115671064A (zh) | 2014-02-07 | 2014-03-07 | 全天然无毒舌下药物递送系统 |
CN201480006550.2A Pending CN105007904A (zh) | 2014-02-07 | 2014-03-07 | 全天然无毒舌下药物递送系统 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201480006550.2A Pending CN105007904A (zh) | 2014-02-07 | 2014-03-07 | 全天然无毒舌下药物递送系统 |
Country Status (10)
Country | Link |
---|---|
US (6) | US20160331693A1 (zh) |
JP (5) | JP2016510345A (zh) |
CN (2) | CN115671064A (zh) |
AU (1) | AU2014331636B2 (zh) |
CA (1) | CA2888219C (zh) |
GB (2) | GB2523480B (zh) |
IL (2) | IL276030B (zh) |
MX (2) | MX2015006022A (zh) |
RU (2) | RU2015112640A (zh) |
WO (1) | WO2015119641A1 (zh) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20160331693A1 (en) * | 2014-02-07 | 2016-11-17 | Scilabs Pharmaceuticals | All natural, non-toxic sublingual drug delievery systems |
US20200197366A1 (en) * | 2017-08-08 | 2020-06-25 | Kashiv Biosciences, Llc | Pharmaceutical composition comprising eliglustat |
Family Cites Families (35)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2205837A (en) * | 1937-03-12 | 1940-06-25 | Abbott Lab | Capsule making machine |
ZA725808B (en) * | 1971-08-24 | 1973-05-30 | Bayer Ag | A coronary agent in special form and processes for its manufacture |
US4576284A (en) * | 1983-12-02 | 1986-03-18 | Warner-Lambert Company | Closing of filled capsules |
ATE120362T1 (de) * | 1989-01-26 | 1995-04-15 | Scherer Corp R P | Texturierte weichkapseln und verfahren und vorrichtung zur herstellung. |
ES2169558T3 (es) * | 1997-10-03 | 2002-07-01 | Warner Lambert Co | Pastilla de nitroglicerina comprimida y metodo para su produccion. |
US6974590B2 (en) * | 1998-03-27 | 2005-12-13 | Cima Labs Inc. | Sublingual buccal effervescent |
US6200604B1 (en) * | 1998-03-27 | 2001-03-13 | Cima Labs Inc. | Sublingual buccal effervescent |
SE9803239D0 (sv) * | 1998-09-24 | 1998-09-24 | Diabact Ab | Composition for the treatment of acute pain |
US6316029B1 (en) * | 2000-05-18 | 2001-11-13 | Flak Pharma International, Ltd. | Rapidly disintegrating solid oral dosage form |
US6495154B1 (en) * | 2000-11-21 | 2002-12-17 | Vivus Inc. | On demand administration of clomipramine and salts thereof to treat premature ejaculation |
IL157320A0 (en) * | 2001-02-08 | 2004-02-19 | Pharmacia Corp | Rapid-onset medicament for the treatment of sexual dysfunction |
US20040052843A1 (en) * | 2001-12-24 | 2004-03-18 | Lerner E. Itzhak | Controlled release dosage forms |
CA2476250C (en) * | 2002-02-13 | 2010-08-03 | Michael K. Weibel | Drug dose-form and method of manufacture |
TW200502000A (en) * | 2003-03-28 | 2005-01-16 | Kyowa Hakko Kogyo Kk | Dividing tablet |
EP1638533A1 (en) * | 2003-06-18 | 2006-03-29 | John Michael Newton | Controlled release devices with lumens |
EP1656102A2 (en) * | 2003-08-21 | 2006-05-17 | Transoral Pharmaceuticals, Inc. | Compositions for delivering 5-ht agonists across the oral mucosa and methods of use thereof |
KR20130006523A (ko) * | 2004-02-17 | 2013-01-16 | 트랜스셉트 파마슈티칼스, 인코포레이티드 | 구강 점막을 가로지르는 수면제 전달용 조성물 및 이의 사용 방법 |
AU2005222613B2 (en) * | 2004-03-12 | 2009-12-17 | Biodel, Inc. | Rapid acting drug delivery compositions |
WO2006004069A1 (ja) * | 2004-07-01 | 2006-01-12 | Ngk Insulators, Ltd. | 微小カプセルおよびその製造方法 |
CA2609330A1 (en) * | 2005-05-25 | 2006-11-30 | Transcept Pharmaceuticals, Inc. | Solid compositions and methods for treating middle-of-the night insomnia |
US20070031349A1 (en) * | 2005-06-23 | 2007-02-08 | David Monteith | Rapidly absorbing oral formulations of PDE 5 inhibitors |
FR2894475B1 (fr) * | 2005-12-14 | 2008-05-16 | Servier Lab | Composition pharmaceutique orodispersible pour administra- -tion oromucosale ou sublinguale d'agomelatine |
US8865743B2 (en) * | 2006-01-06 | 2014-10-21 | Acelrx Pharmaceuticals, Inc. | Small volume oral transmucosal dosage forms containing sufentanil for treatment of pain |
WO2007142811A2 (en) * | 2006-05-19 | 2007-12-13 | Somaxon Pharmaceuticals, Inc. | Low dose doxepin formulations, including buccal, sublingual and fastmelt formulations, and uses of the same to treat insomnia |
US20070286900A1 (en) * | 2006-06-09 | 2007-12-13 | Catherine Herry | Low dose tablets of opioid analgesics and preparation process |
WO2009002084A2 (en) * | 2007-06-27 | 2008-12-31 | Hanmi Pharm. Co., Ltd. | Method for preparing rapidly disintegrating formulation for oral administration and apparatus for preparing and packing the same |
US20090047350A1 (en) * | 2007-08-17 | 2009-02-19 | Ramesh Bangalore | Perforated water soluble polymer based edible films |
CN101579320A (zh) * | 2008-05-12 | 2009-11-18 | 张正生 | 一种枸橼酸西地那非舌下片及其制备方法 |
JP5499599B2 (ja) * | 2008-10-01 | 2014-05-21 | 大正製薬株式会社 | アセトアミノフェン含有錠剤 |
BRPI1010639A2 (pt) * | 2009-05-13 | 2016-03-15 | Protein Delivery Solutions Llc | sistema farmacêutico para distribuição transmembrana |
US8858210B2 (en) * | 2009-09-24 | 2014-10-14 | Mcneil-Ppc, Inc. | Manufacture of variable density dosage forms utilizing radiofrequency energy |
AU2011333683A1 (en) * | 2010-11-25 | 2013-05-09 | Aop Orphan Pharmaceuticals Ag | Fast disintegrating compositions comprising nabilone and randomly methylated beta cyclodextrin |
AR084865A1 (es) * | 2011-01-17 | 2013-07-10 | Takeda Pharmaceutical | Preparacion de desintegracion rapida, comprimido dispersable por via oral |
WO2012146314A1 (en) * | 2011-04-29 | 2012-11-01 | Refarmed Chemicals Sa | Thin gelatin capsules for rapid drug release in the mouth |
US20160331693A1 (en) * | 2014-02-07 | 2016-11-17 | Scilabs Pharmaceuticals | All natural, non-toxic sublingual drug delievery systems |
-
2014
- 2014-03-07 US US14/760,311 patent/US20160331693A1/en not_active Abandoned
- 2014-03-07 AU AU2014331636A patent/AU2014331636B2/en active Active
- 2014-03-07 CN CN202211170568.9A patent/CN115671064A/zh active Pending
- 2014-03-07 RU RU2015112640A patent/RU2015112640A/ru unknown
- 2014-03-07 CA CA2888219A patent/CA2888219C/en active Active
- 2014-03-07 JP JP2015561738A patent/JP2016510345A/ja active Pending
- 2014-03-07 WO PCT/US2014/022054 patent/WO2015119641A1/en active Application Filing
- 2014-03-07 RU RU2017127022A patent/RU2733468C2/ru active
- 2014-03-07 MX MX2015006022A patent/MX2015006022A/es unknown
- 2014-03-07 IL IL276030A patent/IL276030B/en unknown
- 2014-03-07 CN CN201480006550.2A patent/CN105007904A/zh active Pending
- 2014-03-07 GB GB1506043.7A patent/GB2523480B/en active Active
-
2015
- 2015-04-12 IL IL238231A patent/IL238231A0/en unknown
- 2015-05-13 MX MX2021009421A patent/MX2021009421A/es unknown
-
2016
- 2016-09-07 JP JP2016174278A patent/JP2016199601A/ja active Pending
-
2017
- 2017-06-02 US US15/613,057 patent/US20170266118A1/en not_active Abandoned
- 2017-09-04 GB GBGB1714163.1A patent/GB201714163D0/en not_active Ceased
- 2017-12-04 JP JP2017232629A patent/JP2018030896A/ja not_active Ceased
-
2019
- 2019-02-15 US US16/277,070 patent/US20190175513A1/en not_active Abandoned
-
2020
- 2020-05-22 JP JP2020089530A patent/JP2020122024A/ja not_active Withdrawn
-
2021
- 2021-08-12 JP JP2021131622A patent/JP2021178868A/ja active Pending
- 2021-09-01 US US17/464,616 patent/US20210401758A1/en not_active Abandoned
- 2021-09-01 US US17/464,587 patent/US20210401757A1/en active Pending
- 2021-11-10 US US17/523,814 patent/US20220062189A1/en not_active Abandoned
Also Published As
Publication number | Publication date |
---|---|
AU2014331636A1 (en) | 2015-08-27 |
US20170266118A1 (en) | 2017-09-21 |
GB201714163D0 (en) | 2017-10-18 |
JP2020122024A (ja) | 2020-08-13 |
RU2017127022A (ru) | 2019-01-31 |
RU2733468C2 (ru) | 2020-10-01 |
MX2015006022A (es) | 2015-10-14 |
GB201506043D0 (en) | 2015-05-27 |
AU2014331636B2 (en) | 2016-06-02 |
JP2016199601A (ja) | 2016-12-01 |
CN105007904A (zh) | 2015-10-28 |
IL276030A (en) | 2020-08-31 |
US20160331693A1 (en) | 2016-11-17 |
WO2015119641A1 (en) | 2015-08-13 |
RU2017127022A3 (zh) | 2019-12-05 |
JP2016510345A (ja) | 2016-04-07 |
GB2523480B (en) | 2018-06-27 |
GB2523480A (en) | 2015-08-26 |
JP2018030896A (ja) | 2018-03-01 |
US20210401758A1 (en) | 2021-12-30 |
MX2021009421A (es) | 2021-09-10 |
JP2021178868A (ja) | 2021-11-18 |
US20210401757A1 (en) | 2021-12-30 |
US20190175513A1 (en) | 2019-06-13 |
CA2888219C (en) | 2018-07-10 |
IL276030B (en) | 2022-09-01 |
CA2888219A1 (en) | 2015-08-07 |
RU2015112640A (ru) | 2017-02-28 |
IL238231A0 (en) | 2015-05-31 |
US20220062189A1 (en) | 2022-03-03 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP2490676B1 (en) | Pharmaceutical compositions of pde-5 inhibitors and dapoxetine | |
EP2464358B1 (en) | Improved pharmacokinetics of s-adenosylmethionine formulations | |
KR100930329B1 (ko) | 6-머캅토퓨린의 개선된 제제 | |
US20220062189A1 (en) | Sublingual Delivery for Mitigation of Side Effects Associated with Sildenafil Citrate | |
AU2016224503A1 (en) | Solid preparation | |
US20120183607A1 (en) | Stable dosage forms of spiro and dispiro 1,2,4-trioxolane antimalarials | |
CA2889283C (en) | Prolonged-release diphenidol composition | |
KR102239291B1 (ko) | 타다라필 또는 이의 약학적으로 허용가능한 염을 포함하는 저작정 제제 | |
KR101633292B1 (ko) | 용법이 개선된 엔테카비어를 함유하는 약학적 조성물 | |
EP2959891A1 (en) | Modified release pharmaceutical compositions of sofosbuvir and ribavirin | |
US20220023223A1 (en) | Sublingual delivery for mitigation of side effects associated with blonanserin | |
US20220096387A1 (en) | Sublingual delivery for mitigation of side effects associated with lurasidone | |
US20220117900A1 (en) | Sublingual delivery for mitigation of side effects associated with vortioxetine | |
US20220117901A1 (en) | Sublingual delivery for mitigation of side effects associated with brexpiprazole | |
US20220168226A1 (en) | Sublingual delivery for mitigation of side effects associated with metformin | |
US20230114360A1 (en) | Sublingual Delivery for Mitigation of Side Effects Associated with Zicronapine | |
JP2007023043A (ja) | 睡眠薬の放出制御医薬組成物及びその製造方法 | |
US10517914B2 (en) | Healthy tan type of antioxidant defense | |
EP2959888A1 (en) | A novel pharmaceutical composition of sofosbuvir and ribavirin | |
RU2593570C1 (ru) | Противовирусное и иммуностимулирующее лекарственное средство | |
JPH10338634A (ja) | 医薬組成物 | |
JP2019031461A (ja) | 口腔内崩壊錠の製造方法 | |
WO2015063669A1 (en) | Pharmaceutical compositions comprising combination of roflumilast and acebrophylline or pharmaceutically acceptable salts thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20230203 |