US20030175355A1 - Fast melt multiparticulate formulations for oral delivery - Google Patents
Fast melt multiparticulate formulations for oral delivery Download PDFInfo
- Publication number
- US20030175355A1 US20030175355A1 US10/383,351 US38335103A US2003175355A1 US 20030175355 A1 US20030175355 A1 US 20030175355A1 US 38335103 A US38335103 A US 38335103A US 2003175355 A1 US2003175355 A1 US 2003175355A1
- Authority
- US
- United States
- Prior art keywords
- formulation
- drug formulation
- drug
- particles
- 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.)
- Abandoned
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 204
- 238000009472 formulation Methods 0.000 title claims abstract description 136
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 103
- 239000002245 particle Substances 0.000 claims abstract description 102
- 239000013543 active substance Substances 0.000 claims abstract description 92
- 239000013583 drug formulation Substances 0.000 claims abstract description 82
- 230000008021 deposition Effects 0.000 claims abstract description 30
- 239000012530 fluid Substances 0.000 claims abstract description 29
- 230000002496 gastric effect Effects 0.000 claims abstract description 28
- 238000011260 co-administration Methods 0.000 claims abstract description 13
- 239000003814 drug Substances 0.000 claims description 103
- 229940079593 drug Drugs 0.000 claims description 94
- 238000000034 method Methods 0.000 claims description 65
- 239000011230 binding agent Substances 0.000 claims description 56
- 239000000463 material Substances 0.000 claims description 48
- 238000000576 coating method Methods 0.000 claims description 44
- 239000011248 coating agent Substances 0.000 claims description 42
- 210000000214 mouth Anatomy 0.000 claims description 42
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 claims description 38
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 34
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 34
- 239000000811 xylitol Substances 0.000 claims description 34
- 235000010447 xylitol Nutrition 0.000 claims description 34
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 34
- 229960002675 xylitol Drugs 0.000 claims description 34
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical group OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 claims description 33
- 229960005489 paracetamol Drugs 0.000 claims description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 25
- 239000007771 core particle Substances 0.000 claims description 24
- 239000000155 melt Substances 0.000 claims description 23
- 238000002844 melting Methods 0.000 claims description 21
- 230000008018 melting Effects 0.000 claims description 21
- 238000012377 drug delivery Methods 0.000 claims description 20
- 239000004386 Erythritol Substances 0.000 claims description 18
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 claims description 18
- 235000019414 erythritol Nutrition 0.000 claims description 18
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 claims description 18
- 229940009714 erythritol Drugs 0.000 claims description 18
- 210000004072 lung Anatomy 0.000 claims description 16
- 229920002472 Starch Polymers 0.000 claims description 12
- 239000003795 chemical substances by application Substances 0.000 claims description 12
- 235000019698 starch Nutrition 0.000 claims description 12
- -1 succinic acid, acid anhydrides Chemical class 0.000 claims description 12
- 229920001223 polyethylene glycol Polymers 0.000 claims description 11
- 239000008107 starch Substances 0.000 claims description 10
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 9
- 230000002829 reductive effect Effects 0.000 claims description 9
- 239000002202 Polyethylene glycol Substances 0.000 claims description 8
- 150000005846 sugar alcohols Chemical class 0.000 claims description 8
- 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 claims description 7
- 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 claims description 7
- 229930195725 Mannitol Natural products 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 7
- 150000001720 carbohydrates Chemical class 0.000 claims description 7
- 238000000354 decomposition reaction Methods 0.000 claims description 7
- 238000005469 granulation Methods 0.000 claims description 7
- 230000003179 granulation Effects 0.000 claims description 7
- 239000000594 mannitol Substances 0.000 claims description 7
- 235000010355 mannitol Nutrition 0.000 claims description 7
- WBZFUFAFFUEMEI-UHFFFAOYSA-M Acesulfame k Chemical compound [K+].CC1=CC(=O)[N-]S(=O)(=O)O1 WBZFUFAFFUEMEI-UHFFFAOYSA-M 0.000 claims description 6
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 claims description 6
- 108010010803 Gelatin Proteins 0.000 claims description 6
- 241001465754 Metazoa Species 0.000 claims description 6
- 239000008273 gelatin Substances 0.000 claims description 6
- 229920000159 gelatin Polymers 0.000 claims description 6
- 235000019322 gelatine Nutrition 0.000 claims description 6
- 235000011852 gelatine desserts Nutrition 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 5
- 239000001856 Ethyl cellulose Substances 0.000 claims description 5
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 5
- 229920001249 ethyl cellulose Polymers 0.000 claims description 5
- 235000003599 food sweetener Nutrition 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 239000003765 sweetening agent Substances 0.000 claims description 5
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- 235000010643 Leucaena leucocephala Nutrition 0.000 claims description 4
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 4
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 4
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 claims description 4
- 238000013270 controlled release Methods 0.000 claims description 4
- 239000012729 immediate-release (IR) formulation Substances 0.000 claims description 4
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 4
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical group C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 claims description 4
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 claims description 3
- 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 claims 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 claims description 3
- 229920002307 Dextran Polymers 0.000 claims description 3
- 229920001353 Dextrin Polymers 0.000 claims description 3
- 239000004375 Dextrin Substances 0.000 claims description 3
- 108010016626 Dipeptides Proteins 0.000 claims description 3
- 229940072056 alginate Drugs 0.000 claims description 3
- 235000010443 alginic acid Nutrition 0.000 claims description 3
- 229920000615 alginic acid Polymers 0.000 claims description 3
- 239000003242 anti bacterial agent Substances 0.000 claims description 3
- 239000008122 artificial sweetener Substances 0.000 claims description 3
- 235000021311 artificial sweeteners Nutrition 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 claims description 3
- 235000015165 citric acid Nutrition 0.000 claims description 3
- 229960002626 clarithromycin Drugs 0.000 claims description 3
- AGOYDEPGAOXOCK-KCBOHYOISA-N clarithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@](C)([C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)OC)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 AGOYDEPGAOXOCK-KCBOHYOISA-N 0.000 claims description 3
- 235000019425 dextrin Nutrition 0.000 claims description 3
- 229960003276 erythromycin Drugs 0.000 claims description 3
- 239000000845 maltitol Substances 0.000 claims description 3
- 235000010449 maltitol Nutrition 0.000 claims description 3
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 claims description 3
- 229940035436 maltitol Drugs 0.000 claims description 3
- 229920000193 polymethacrylate Polymers 0.000 claims description 3
- 229920006316 polyvinylpyrrolidine Polymers 0.000 claims description 3
- 239000000600 sorbitol Substances 0.000 claims description 3
- 235000010356 sorbitol Nutrition 0.000 claims description 3
- 238000013268 sustained release Methods 0.000 claims description 3
- 239000012730 sustained-release form Substances 0.000 claims description 3
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 2
- 229920000623 Cellulose acetate phthalate Polymers 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- 229920001800 Shellac Polymers 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- 239000001361 adipic acid Substances 0.000 claims description 2
- 235000011037 adipic acid Nutrition 0.000 claims description 2
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims description 2
- 150000008041 alkali metal carbonates Chemical class 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
- 239000002585 base Substances 0.000 claims description 2
- GSHUZVSNIBLGMR-UHFFFAOYSA-N calcium;1,1-dioxo-1,2-benzothiazol-3-one Chemical class [Ca].C1=CC=C2C(=O)NS(=O)(=O)C2=C1 GSHUZVSNIBLGMR-UHFFFAOYSA-N 0.000 claims description 2
- 229940081734 cellulose acetate phthalate Drugs 0.000 claims description 2
- HCAJEUSONLESMK-UHFFFAOYSA-N cyclohexylsulfamic acid Chemical class OS(=O)(=O)NC1CCCCC1 HCAJEUSONLESMK-UHFFFAOYSA-N 0.000 claims description 2
- 239000001530 fumaric acid Substances 0.000 claims description 2
- 235000011087 fumaric acid Nutrition 0.000 claims description 2
- 239000008240 homogeneous mixture Substances 0.000 claims description 2
- 239000001630 malic acid Substances 0.000 claims description 2
- 235000011090 malic acid Nutrition 0.000 claims description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 claims description 2
- 235000019204 saccharin Nutrition 0.000 claims description 2
- 229940081974 saccharin Drugs 0.000 claims description 2
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 claims description 2
- 239000004208 shellac Substances 0.000 claims description 2
- 229940113147 shellac Drugs 0.000 claims description 2
- 235000013874 shellac Nutrition 0.000 claims description 2
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 2
- 239000003120 macrolide antibiotic agent Substances 0.000 claims 7
- 230000003111 delayed effect Effects 0.000 claims 3
- 230000003115 biocidal effect Effects 0.000 claims 2
- RXZBMPWDPOLZGW-XMRMVWPWSA-N (E)-roxithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=N/OCOCCOC)/[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 RXZBMPWDPOLZGW-XMRMVWPWSA-N 0.000 claims 1
- 241000220479 Acacia Species 0.000 claims 1
- DMUAPQTXSSNEDD-QALJCMCCSA-N Midecamycin Chemical compound C1[C@](O)(C)[C@@H](OC(=O)CC)[C@H](C)O[C@H]1O[C@H]1[C@H](N(C)C)[C@@H](O)[C@H](O[C@@H]2[C@H]([C@H](OC(=O)CC)CC(=O)O[C@H](C)C/C=C/C=C/[C@H](O)[C@H](C)C[C@@H]2CC=O)OC)O[C@@H]1C DMUAPQTXSSNEDD-QALJCMCCSA-N 0.000 claims 1
- 239000004104 Oleandomycin Substances 0.000 claims 1
- RZPAKFUAFGMUPI-UHFFFAOYSA-N Oleandomycin Natural products O1C(C)C(O)C(OC)CC1OC1C(C)C(=O)OC(C)C(C)C(O)C(C)C(=O)C2(OC2)CC(C)C(OC2C(C(CC(C)O2)N(C)C)O)C1C RZPAKFUAFGMUPI-UHFFFAOYSA-N 0.000 claims 1
- VYWWNRMSAPEJLS-MDWYKHENSA-N Rokitamycin Chemical compound C1[C@](OC(=O)CC)(C)[C@@H](OC(=O)CCC)[C@H](C)O[C@H]1O[C@H]1[C@H](N(C)C)[C@@H](O)[C@H](O[C@@H]2[C@H]([C@H](O)CC(=O)O[C@H](C)C/C=C/C=C/[C@H](O)[C@H](C)C[C@@H]2CC=O)OC)O[C@@H]1C VYWWNRMSAPEJLS-MDWYKHENSA-N 0.000 claims 1
- 239000004182 Tylosin Substances 0.000 claims 1
- 229930194936 Tylosin Natural products 0.000 claims 1
- 229960004099 azithromycin Drugs 0.000 claims 1
- MQTOSJVFKKJCRP-BICOPXKESA-N azithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)N(C)C[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 MQTOSJVFKKJCRP-BICOPXKESA-N 0.000 claims 1
- 229960004100 dirithromycin Drugs 0.000 claims 1
- WLOHNSSYAXHWNR-NXPDYKKBSA-N dirithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H]2O[C@H](COCCOC)N[C@H]([C@@H]2C)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 WLOHNSSYAXHWNR-NXPDYKKBSA-N 0.000 claims 1
- 229960001398 flurithromycin Drugs 0.000 claims 1
- XOEUHCONYHZURQ-HNUBZJOYSA-N flurithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@@](C)(F)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 XOEUHCONYHZURQ-HNUBZJOYSA-N 0.000 claims 1
- 230000002209 hydrophobic effect Effects 0.000 claims 1
- 229960004144 josamycin Drugs 0.000 claims 1
- XJSFLOJWULLJQS-NGVXBBESSA-N josamycin Chemical compound CO[C@H]1[C@H](OC(C)=O)CC(=O)O[C@H](C)C\C=C\C=C\[C@H](O)[C@H](C)C[C@H](CC=O)[C@@H]1O[C@H]1[C@H](O)[C@@H](N(C)C)[C@H](O[C@@H]2O[C@@H](C)[C@H](OC(=O)CC(C)C)[C@](C)(O)C2)[C@@H](C)O1 XJSFLOJWULLJQS-NGVXBBESSA-N 0.000 claims 1
- 229950007634 kitasamycin Drugs 0.000 claims 1
- XYJOGTQLTFNMQG-KJHBSLKPSA-N leucomycin V Chemical compound CO[C@H]1[C@H](O)CC(=O)O[C@H](C)C\C=C\C=C\[C@H](O)[C@H](C)C[C@H](CC=O)[C@@H]1O[C@H]1[C@H](O)[C@@H](N(C)C)[C@H](O[C@@H]2O[C@@H](C)[C@H](O)[C@](C)(O)C2)[C@@H](C)O1 XYJOGTQLTFNMQG-KJHBSLKPSA-N 0.000 claims 1
- 229960002757 midecamycin Drugs 0.000 claims 1
- 229960000931 miocamycin Drugs 0.000 claims 1
- GQNZGCARKRHPOH-RQIKCTSVSA-N miocamycin Chemical compound C1[C@](OC(C)=O)(C)[C@@H](OC(=O)CC)[C@H](C)O[C@H]1O[C@H]1[C@H](N(C)C)[C@@H](O)[C@H](O[C@@H]2[C@H]([C@H](OC(=O)CC)CC(=O)O[C@H](C)C/C=C/C=C/[C@H](OC(C)=O)[C@H](C)C[C@@H]2CC=O)OC)O[C@@H]1C GQNZGCARKRHPOH-RQIKCTSVSA-N 0.000 claims 1
- 229960002351 oleandomycin Drugs 0.000 claims 1
- RZPAKFUAFGMUPI-KGIGTXTPSA-N oleandomycin Chemical compound O1[C@@H](C)[C@H](O)[C@@H](OC)C[C@@H]1O[C@@H]1[C@@H](C)C(=O)O[C@H](C)[C@H](C)[C@H](O)[C@@H](C)C(=O)[C@]2(OC2)C[C@H](C)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C RZPAKFUAFGMUPI-KGIGTXTPSA-N 0.000 claims 1
- 235000019367 oleandomycin Nutrition 0.000 claims 1
- 229960001170 rokitamycin Drugs 0.000 claims 1
- IUPCWCLVECYZRV-JZMZINANSA-N rosaramicin Chemical compound O([C@@H]1[C@@H](C)[C@H](O)CC(=O)O[C@@H]([C@H]([C@@H]2O[C@@]2(C)/C=C/C(=O)[C@H](C)C[C@@H]1CC=O)C)CC)[C@@H]1O[C@H](C)C[C@H](N(C)C)[C@H]1O IUPCWCLVECYZRV-JZMZINANSA-N 0.000 claims 1
- 229950001447 rosaramicin Drugs 0.000 claims 1
- 229960005224 roxithromycin Drugs 0.000 claims 1
- 239000000758 substrate Substances 0.000 claims 1
- 229960004059 tylosin Drugs 0.000 claims 1
- WBPYTXDJUQJLPQ-VMXQISHHSA-N tylosin Chemical compound O([C@@H]1[C@@H](C)O[C@H]([C@@H]([C@H]1N(C)C)O)O[C@@H]1[C@@H](C)[C@H](O)CC(=O)O[C@@H]([C@H](/C=C(\C)/C=C/C(=O)[C@H](C)C[C@@H]1CC=O)CO[C@H]1[C@@H]([C@H](OC)[C@H](O)[C@@H](C)O1)OC)CC)[C@H]1C[C@@](C)(O)[C@@H](O)[C@H](C)O1 WBPYTXDJUQJLPQ-VMXQISHHSA-N 0.000 claims 1
- 235000019375 tylosin Nutrition 0.000 claims 1
- 108010011485 Aspartame Proteins 0.000 description 31
- 239000000605 aspartame Substances 0.000 description 31
- 235000010357 aspartame Nutrition 0.000 description 31
- 229960003438 aspartame Drugs 0.000 description 31
- 239000000843 powder Substances 0.000 description 25
- 238000002156 mixing Methods 0.000 description 22
- 229920002774 Maltodextrin Polymers 0.000 description 20
- 239000005913 Maltodextrin Substances 0.000 description 20
- 229940035034 maltodextrin Drugs 0.000 description 20
- 239000008187 granular material Substances 0.000 description 18
- 238000009826 distribution Methods 0.000 description 17
- 238000004090 dissolution Methods 0.000 description 16
- 239000006185 dispersion Substances 0.000 description 15
- 239000008118 PEG 6000 Substances 0.000 description 13
- 229920002584 Polyethylene Glycol 6000 Polymers 0.000 description 13
- 239000002552 dosage form Substances 0.000 description 13
- YASYEJJMZJALEJ-UHFFFAOYSA-N Citric acid monohydrate Chemical compound O.OC(=O)CC(O)(C(O)=O)CC(O)=O YASYEJJMZJALEJ-UHFFFAOYSA-N 0.000 description 11
- 229960002303 citric acid monohydrate Drugs 0.000 description 11
- RRPFCKLVOUENJB-UHFFFAOYSA-L disodium;2-aminoacetic acid;carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O.NCC(O)=O RRPFCKLVOUENJB-UHFFFAOYSA-L 0.000 description 10
- 239000003826 tablet Substances 0.000 description 10
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 9
- 229910052700 potassium Inorganic materials 0.000 description 9
- 239000011591 potassium Substances 0.000 description 9
- 229940032147 starch Drugs 0.000 description 9
- 239000011521 glass Substances 0.000 description 8
- 239000007909 solid dosage form Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- DBAKFASWICGISY-BTJKTKAUSA-N Chlorpheniramine maleate Chemical compound OC(=O)\C=C/C(O)=O.C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 DBAKFASWICGISY-BTJKTKAUSA-N 0.000 description 7
- 108090000790 Enzymes Proteins 0.000 description 7
- 102000004190 Enzymes Human genes 0.000 description 7
- 229940046978 chlorpheniramine maleate Drugs 0.000 description 7
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 7
- 229940088598 enzyme Drugs 0.000 description 7
- 239000013020 final formulation Substances 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 7
- 238000007909 melt granulation Methods 0.000 description 7
- 230000002685 pulmonary effect Effects 0.000 description 7
- 238000011282 treatment Methods 0.000 description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 230000008901 benefit Effects 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 238000010348 incorporation Methods 0.000 description 6
- 238000007873 sieving Methods 0.000 description 6
- 239000007921 spray Substances 0.000 description 6
- 229940124597 therapeutic agent Drugs 0.000 description 6
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 5
- 206010013911 Dysgeusia Diseases 0.000 description 5
- 241000124008 Mammalia Species 0.000 description 5
- 229960001138 acetylsalicylic acid Drugs 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 230000015556 catabolic process Effects 0.000 description 5
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 5
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 238000005507 spraying Methods 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 230000004584 weight gain Effects 0.000 description 5
- 235000019786 weight gain Nutrition 0.000 description 5
- 241000282412 Homo Species 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 235000010358 acesulfame potassium Nutrition 0.000 description 4
- 229960004998 acesulfame potassium Drugs 0.000 description 4
- 239000000619 acesulfame-K Substances 0.000 description 4
- 238000006731 degradation reaction Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000010419 fine particle Substances 0.000 description 4
- 238000007757 hot melt coating Methods 0.000 description 4
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000008109 sodium starch glycolate Substances 0.000 description 4
- 229920003109 sodium starch glycolate Polymers 0.000 description 4
- 229940079832 sodium starch glycolate Drugs 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-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 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
- 240000007472 Leucaena leucocephala Species 0.000 description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 3
- 239000006057 Non-nutritive feed additive Substances 0.000 description 3
- 206010039424 Salivary hypersecretion Diseases 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- BNQDCRGUHNALGH-UHFFFAOYSA-N benserazide Chemical compound OCC(N)C(=O)NNCC1=CC=C(O)C(O)=C1O BNQDCRGUHNALGH-UHFFFAOYSA-N 0.000 description 3
- 239000003172 expectorant agent Substances 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 239000012669 liquid formulation Substances 0.000 description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 3
- 239000008108 microcrystalline cellulose Substances 0.000 description 3
- 239000006186 oral dosage form Substances 0.000 description 3
- 239000008184 oral solid dosage form Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- VMXUWOKSQNHOCA-LCYFTJDESA-N ranitidine Chemical compound [O-][N+](=O)/C=C(/NC)NCCSCC1=CC=C(CN(C)C)O1 VMXUWOKSQNHOCA-LCYFTJDESA-N 0.000 description 3
- 229960000620 ranitidine Drugs 0.000 description 3
- 239000000932 sedative agent Substances 0.000 description 3
- 229940125723 sedative agent Drugs 0.000 description 3
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 description 2
- 208000002310 Achlorhydria Diseases 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 235000005979 Citrus limon Nutrition 0.000 description 2
- 244000131522 Citrus pyriformis Species 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 239000005977 Ethylene Substances 0.000 description 2
- 229920003134 Eudragit® polymer Polymers 0.000 description 2
- 108010073178 Glucan 1,4-alpha-Glucosidase Proteins 0.000 description 2
- RPTUSVTUFVMDQK-UHFFFAOYSA-N Hidralazin Chemical compound C1=CC=C2C(NN)=NN=CC2=C1 RPTUSVTUFVMDQK-UHFFFAOYSA-N 0.000 description 2
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 2
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 2
- 208000019695 Migraine disease Diseases 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-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
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 229960000723 ampicillin Drugs 0.000 description 2
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 2
- 229940035676 analgesics Drugs 0.000 description 2
- 229940069428 antacid Drugs 0.000 description 2
- 239000003159 antacid agent Substances 0.000 description 2
- 239000000730 antalgic agent Substances 0.000 description 2
- 230000001088 anti-asthma Effects 0.000 description 2
- 230000001387 anti-histamine Effects 0.000 description 2
- 230000002924 anti-infective effect Effects 0.000 description 2
- 239000000924 antiasthmatic agent Substances 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 239000001961 anticonvulsive agent Substances 0.000 description 2
- 239000003434 antitussive agent Substances 0.000 description 2
- 229940124584 antitussives Drugs 0.000 description 2
- 239000002249 anxiolytic agent Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000003125 aqueous solvent Substances 0.000 description 2
- 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 2
- 229940124630 bronchodilator Drugs 0.000 description 2
- 230000002308 calcification Effects 0.000 description 2
- 235000014633 carbohydrates Nutrition 0.000 description 2
- 229940106164 cephalexin Drugs 0.000 description 2
- ZAIPMKNFIOOWCQ-UEKVPHQBSA-N cephalexin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CC=CC=C1 ZAIPMKNFIOOWCQ-UEKVPHQBSA-N 0.000 description 2
- 230000002490 cerebral effect Effects 0.000 description 2
- 229960003291 chlorphenamine Drugs 0.000 description 2
- SOYKEARSMXGVTM-UHFFFAOYSA-N chlorphenamine Chemical compound C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 SOYKEARSMXGVTM-UHFFFAOYSA-N 0.000 description 2
- 229960004106 citric acid Drugs 0.000 description 2
- 238000011109 contamination Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000003218 coronary vasodilator agent Substances 0.000 description 2
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 description 2
- 239000000850 decongestant Substances 0.000 description 2
- 230000000593 degrading effect Effects 0.000 description 2
- 229960001259 diclofenac Drugs 0.000 description 2
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 239000002934 diuretic Substances 0.000 description 2
- 229960001253 domperidone Drugs 0.000 description 2
- FGXWKSZFVQUSTL-UHFFFAOYSA-N domperidone Chemical compound C12=CC=CC=C2NC(=O)N1CCCN(CC1)CCC1N1C2=CC=C(Cl)C=C2NC1=O FGXWKSZFVQUSTL-UHFFFAOYSA-N 0.000 description 2
- 230000003419 expectorant effect Effects 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000019634 flavors Nutrition 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
- 238000004108 freeze drying Methods 0.000 description 2
- 210000005095 gastrointestinal system Anatomy 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 239000001087 glyceryl triacetate Substances 0.000 description 2
- 235000013773 glyceryl triacetate Nutrition 0.000 description 2
- LNEPOXFFQSENCJ-UHFFFAOYSA-N haloperidol Chemical compound C1CC(O)(C=2C=CC(Cl)=CC=2)CCN1CCCC(=O)C1=CC=C(F)C=C1 LNEPOXFFQSENCJ-UHFFFAOYSA-N 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- 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 2
- 230000000147 hypnotic effect Effects 0.000 description 2
- 229960001680 ibuprofen Drugs 0.000 description 2
- 229960000905 indomethacin Drugs 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 235000015110 jellies Nutrition 0.000 description 2
- 239000008274 jelly Substances 0.000 description 2
- MJIHNNLFOKEZEW-UHFFFAOYSA-N lansoprazole Chemical compound CC1=C(OCC(F)(F)F)C=CN=C1CS(=O)C1=NC2=CC=CC=C2N1 MJIHNNLFOKEZEW-UHFFFAOYSA-N 0.000 description 2
- 229960003174 lansoprazole Drugs 0.000 description 2
- 239000008141 laxative Substances 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 229960001571 loperamide Drugs 0.000 description 2
- RDOIQAHITMMDAJ-UHFFFAOYSA-N loperamide Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(C(=O)N(C)C)CCN(CC1)CCC1(O)C1=CC=C(Cl)C=C1 RDOIQAHITMMDAJ-UHFFFAOYSA-N 0.000 description 2
- 230000000873 masking effect Effects 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 206010027599 migraine Diseases 0.000 description 2
- 239000003595 mist Substances 0.000 description 2
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 2
- 229940066491 mucolytics Drugs 0.000 description 2
- 230000002232 neuromuscular Effects 0.000 description 2
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 2
- 229960002085 oxycodone Drugs 0.000 description 2
- XQYZDYMELSJDRZ-UHFFFAOYSA-N papaverine Chemical compound C1=C(OC)C(OC)=CC=C1CC1=NC=CC2=CC(OC)=C(OC)C=C12 XQYZDYMELSJDRZ-UHFFFAOYSA-N 0.000 description 2
- 230000002093 peripheral effect Effects 0.000 description 2
- DHHVAGZRUROJKS-UHFFFAOYSA-N phentermine Chemical compound CC(C)(N)CC1=CC=CC=C1 DHHVAGZRUROJKS-UHFFFAOYSA-N 0.000 description 2
- 229920000136 polysorbate Polymers 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- LXNHXLLTXMVWPM-UHFFFAOYSA-N pyridoxine Chemical compound CC1=NC=C(CO)C(CO)=C1O LXNHXLLTXMVWPM-UHFFFAOYSA-N 0.000 description 2
- 210000003296 saliva Anatomy 0.000 description 2
- 239000000021 stimulant Substances 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- KQKPFRSPSRPDEB-UHFFFAOYSA-N sumatriptan Chemical compound CNS(=O)(=O)CC1=CC=C2NC=C(CCN(C)C)C2=C1 KQKPFRSPSRPDEB-UHFFFAOYSA-N 0.000 description 2
- 229960003708 sumatriptan Drugs 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 230000009747 swallowing Effects 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 2
- 210000001685 thyroid gland Anatomy 0.000 description 2
- 229960002622 triacetin Drugs 0.000 description 2
- 229940124549 vasodilator Drugs 0.000 description 2
- 239000003071 vasodilator agent Substances 0.000 description 2
- RXPRRQLKFXBCSJ-GIVPXCGWSA-N vincamine Chemical compound C1=CC=C2C(CCN3CCC4)=C5[C@@H]3[C@]4(CC)C[C@](O)(C(=O)OC)N5C2=C1 RXPRRQLKFXBCSJ-GIVPXCGWSA-N 0.000 description 2
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 2
- DBGIVFWFUFKIQN-UHFFFAOYSA-N (+-)-Fenfluramine Chemical compound CCNC(C)CC1=CC=CC(C(F)(F)F)=C1 DBGIVFWFUFKIQN-UHFFFAOYSA-N 0.000 description 1
- JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 description 1
- AKNNEGZIBPJZJG-MSOLQXFVSA-N (-)-noscapine Chemical compound CN1CCC2=CC=3OCOC=3C(OC)=C2[C@@H]1[C@@H]1C2=CC=C(OC)C(OC)=C2C(=O)O1 AKNNEGZIBPJZJG-MSOLQXFVSA-N 0.000 description 1
- YKFCISHFRZHKHY-NGQGLHOPSA-N (2s)-2-amino-3-(3,4-dihydroxyphenyl)-2-methylpropanoic acid;trihydrate Chemical compound O.O.O.OC(=O)[C@](N)(C)CC1=CC=C(O)C(O)=C1.OC(=O)[C@](N)(C)CC1=CC=C(O)C(O)=C1 YKFCISHFRZHKHY-NGQGLHOPSA-N 0.000 description 1
- ZGSZBVAEVPSPFM-HYTSPMEMSA-N (4r,4ar,7s,7ar,12bs)-9-methoxy-3-methyl-2,4,4a,5,6,7,7a,13-octahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-ol;(2r,3r)-2,3-dihydroxybutanedioic acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.C([C@H]1[C@H](N(CC[C@@]112)C)C3)C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC ZGSZBVAEVPSPFM-HYTSPMEMSA-N 0.000 description 1
- DKSZLDSPXIWGFO-BLOJGBSASA-N (4r,4ar,7s,7ar,12bs)-9-methoxy-3-methyl-2,4,4a,7,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-ol;phosphoric acid;hydrate Chemical compound O.OP(O)(O)=O.OP(O)(O)=O.C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC.C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC DKSZLDSPXIWGFO-BLOJGBSASA-N 0.000 description 1
- BCXHDORHMMZBBZ-DORFAMGDSA-N (4r,4ar,7s,7ar,12bs)-9-methoxy-3-methyl-2,4,4a,7,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-ol;sulfuric acid Chemical compound OS(O)(=O)=O.C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC.C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC BCXHDORHMMZBBZ-DORFAMGDSA-N 0.000 description 1
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 1
- 229930182837 (R)-adrenaline Natural products 0.000 description 1
- GJHKWLSRHNWTAN-UHFFFAOYSA-N 1-ethoxy-4-(4-pentylcyclohexyl)benzene Chemical compound C1CC(CCCCC)CCC1C1=CC=C(OCC)C=C1 GJHKWLSRHNWTAN-UHFFFAOYSA-N 0.000 description 1
- SEVKYLYIYIKRSW-UHFFFAOYSA-N 1-phenylpropan-2-ylazanium;chloride Chemical compound Cl.CC(N)CC1=CC=CC=C1 SEVKYLYIYIKRSW-UHFFFAOYSA-N 0.000 description 1
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 description 1
- JIVPVXMEBJLZRO-CQSZACIVSA-N 2-chloro-5-[(1r)-1-hydroxy-3-oxo-2h-isoindol-1-yl]benzenesulfonamide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC([C@@]2(O)C3=CC=CC=C3C(=O)N2)=C1 JIVPVXMEBJLZRO-CQSZACIVSA-N 0.000 description 1
- XLMXUUQMSMKFMH-UZRURVBFSA-N 2-hydroxyethyl (z,12r)-12-hydroxyoctadec-9-enoate Chemical compound CCCCCC[C@@H](O)C\C=C/CCCCCCCC(=O)OCCO XLMXUUQMSMKFMH-UZRURVBFSA-N 0.000 description 1
- RFVNOJDQRGSOEL-UHFFFAOYSA-N 2-hydroxyethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCO RFVNOJDQRGSOEL-UHFFFAOYSA-N 0.000 description 1
- CDOUZKKFHVEKRI-UHFFFAOYSA-N 3-bromo-n-[(prop-2-enoylamino)methyl]propanamide Chemical compound BrCCC(=O)NCNC(=O)C=C CDOUZKKFHVEKRI-UHFFFAOYSA-N 0.000 description 1
- MEAPRSDUXBHXGD-UHFFFAOYSA-N 3-chloro-n-(4-propan-2-ylphenyl)propanamide Chemical compound CC(C)C1=CC=C(NC(=O)CCCl)C=C1 MEAPRSDUXBHXGD-UHFFFAOYSA-N 0.000 description 1
- BSYNRYMUTXBXSQ-FOQJRBATSA-N 59096-14-9 Chemical compound CC(=O)OC1=CC=CC=C1[14C](O)=O BSYNRYMUTXBXSQ-FOQJRBATSA-N 0.000 description 1
- SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 description 1
- CZANOGSGRGNFPB-UHFFFAOYSA-N 8-chloro-1,3-dimethyl-7h-purine-2,6-dione;n,n-dimethyl-3-phenothiazin-10-ylpropan-1-amine Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC(Cl)=N2.C1=CC=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 CZANOGSGRGNFPB-UHFFFAOYSA-N 0.000 description 1
- GJCOSYZMQJWQCA-UHFFFAOYSA-N 9H-xanthene Chemical compound C1=CC=C2CC3=CC=CC=C3OC2=C1 GJCOSYZMQJWQCA-UHFFFAOYSA-N 0.000 description 1
- 229930008281 A03AD01 - Papaverine Natural products 0.000 description 1
- 229930000680 A04AD01 - Scopolamine Natural products 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- OGSPWJRAVKPPFI-UHFFFAOYSA-N Alendronic Acid Chemical compound NCCCC(O)(P(O)(O)=O)P(O)(O)=O OGSPWJRAVKPPFI-UHFFFAOYSA-N 0.000 description 1
- KHOITXIGCFIULA-UHFFFAOYSA-N Alophen Chemical compound C1=CC(OC(=O)C)=CC=C1C(C=1N=CC=CC=1)C1=CC=C(OC(C)=O)C=C1 KHOITXIGCFIULA-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 239000004382 Amylase Substances 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- GHXZTYHSJHQHIJ-UHFFFAOYSA-N Chlorhexidine Chemical compound C=1C=C(Cl)C=CC=1NC(N)=NC(N)=NCCCCCCN=C(N)N=C(N)NC1=CC=C(Cl)C=C1 GHXZTYHSJHQHIJ-UHFFFAOYSA-N 0.000 description 1
- JZUFKLXOESDKRF-UHFFFAOYSA-N Chlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 244000303965 Cyamopsis psoralioides Species 0.000 description 1
- XUIIKFGFIJCVMT-GFCCVEGCSA-N D-thyroxine Chemical compound IC1=CC(C[C@@H](N)C(O)=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-GFCCVEGCSA-N 0.000 description 1
- 208000019505 Deglutition disease Diseases 0.000 description 1
- HCYAFALTSJYZDH-UHFFFAOYSA-N Desimpramine Chemical compound C1CC2=CC=CC=C2N(CCCNC)C2=CC=CC=C21 HCYAFALTSJYZDH-UHFFFAOYSA-N 0.000 description 1
- 229940097420 Diuretic Drugs 0.000 description 1
- YAVZHCFFUATPRK-YZPBMOCRSA-N Erythromycin stearate Chemical compound CCCCCCCCCCCCCCCCCC(O)=O.O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 YAVZHCFFUATPRK-YZPBMOCRSA-N 0.000 description 1
- DBVJJBKOTRCVKF-UHFFFAOYSA-N Etidronic acid Chemical compound OP(=O)(O)C(O)(C)P(O)(O)=O DBVJJBKOTRCVKF-UHFFFAOYSA-N 0.000 description 1
- 229920003135 Eudragit® L 100-55 Polymers 0.000 description 1
- 229920003138 Eudragit® L 30 D-55 Polymers 0.000 description 1
- 229920003151 Eudragit® RL polymer Polymers 0.000 description 1
- 229920003152 Eudragit® RS polymer Polymers 0.000 description 1
- 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 1
- 102000051325 Glucagon Human genes 0.000 description 1
- 108060003199 Glucagon Proteins 0.000 description 1
- HSRJKNPTNIJEKV-UHFFFAOYSA-N Guaifenesin Chemical compound COC1=CC=CC=C1OCC(O)CO HSRJKNPTNIJEKV-UHFFFAOYSA-N 0.000 description 1
- GVGLGOZIDCSQPN-PVHGPHFFSA-N Heroin Chemical compound O([C@H]1[C@H](C=C[C@H]23)OC(C)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4OC(C)=O GVGLGOZIDCSQPN-PVHGPHFFSA-N 0.000 description 1
- STECJAGHUSJQJN-GAUPFVANSA-N Hyoscine Natural products C1([C@H](CO)C(=O)OC2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-GAUPFVANSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 102000004195 Isomerases Human genes 0.000 description 1
- 108090000769 Isomerases Proteins 0.000 description 1
- DHUZAAUGHUHIDS-ONEGZZNKSA-N Isomyristicin Chemical compound COC1=CC(\C=C\C)=CC2=C1OCO2 DHUZAAUGHUHIDS-ONEGZZNKSA-N 0.000 description 1
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 description 1
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- MKXZASYAUGDDCJ-SZMVWBNQSA-N LSM-2525 Chemical compound C1CCC[C@H]2[C@@]3([H])N(C)CC[C@]21C1=CC(OC)=CC=C1C3 MKXZASYAUGDDCJ-SZMVWBNQSA-N 0.000 description 1
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 1
- XADCESSVHJOZHK-UHFFFAOYSA-N Meperidine Chemical compound C=1C=CC=CC=1C1(C(=O)OCC)CCN(C)CC1 XADCESSVHJOZHK-UHFFFAOYSA-N 0.000 description 1
- ROAIXOJGRFKICW-UHFFFAOYSA-N Methenamine hippurate Chemical compound C1N(C2)CN3CN1CN2C3.OC(=O)CNC(=O)C1=CC=CC=C1 ROAIXOJGRFKICW-UHFFFAOYSA-N 0.000 description 1
- DUGOZIWVEXMGBE-UHFFFAOYSA-N Methylphenidate Chemical compound C=1C=CC=CC=1C(C(=O)OC)C1CCCCN1 DUGOZIWVEXMGBE-UHFFFAOYSA-N 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- STECJAGHUSJQJN-UHFFFAOYSA-N N-Methyl-scopolamin Natural products C1C(C2C3O2)N(C)C3CC1OC(=O)C(CO)C1=CC=CC=C1 STECJAGHUSJQJN-UHFFFAOYSA-N 0.000 description 1
- 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
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 1
- SNIOPGDIGTZGOP-UHFFFAOYSA-N Nitroglycerin Chemical compound [O-][N+](=O)OCC(O[N+]([O-])=O)CO[N+]([O-])=O SNIOPGDIGTZGOP-UHFFFAOYSA-N 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- TZRXHJWUDPFEEY-UHFFFAOYSA-N Pentaerythritol Tetranitrate Chemical compound [O-][N+](=O)OCC(CO[N+]([O-])=O)(CO[N+]([O-])=O)CO[N+]([O-])=O TZRXHJWUDPFEEY-UHFFFAOYSA-N 0.000 description 1
- 239000000026 Pentaerythritol tetranitrate Substances 0.000 description 1
- 229920002685 Polyoxyl 35CastorOil Polymers 0.000 description 1
- KNAHARQHSZJURB-UHFFFAOYSA-N Propylthiouracile Chemical compound CCCC1=CC(=O)NC(=S)N1 KNAHARQHSZJURB-UHFFFAOYSA-N 0.000 description 1
- 102000007327 Protamines Human genes 0.000 description 1
- 108010007568 Protamines Proteins 0.000 description 1
- GBFLZEXEOZUWRN-VKHMYHEASA-N S-carboxymethyl-L-cysteine Chemical compound OC(=O)[C@@H](N)CSCC(O)=O GBFLZEXEOZUWRN-VKHMYHEASA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 239000004141 Sodium laurylsulphate Substances 0.000 description 1
- 229930182558 Sterol Natural products 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
- JZRWCGZRTZMZEH-UHFFFAOYSA-N Thiamine Natural products CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N JZRWCGZRTZMZEH-UHFFFAOYSA-N 0.000 description 1
- KLBQZWRITKRQQV-UHFFFAOYSA-N Thioridazine Chemical compound C12=CC(SC)=CC=C2SC2=CC=CC=C2N1CCC1CCCCN1C KLBQZWRITKRQQV-UHFFFAOYSA-N 0.000 description 1
- AUYYCJSJGJYCDS-LBPRGKRZSA-N Thyrolar Chemical compound IC1=CC(C[C@H](N)C(O)=O)=CC(I)=C1OC1=CC=C(O)C(I)=C1 AUYYCJSJGJYCDS-LBPRGKRZSA-N 0.000 description 1
- JLRGJRBPOGGCBT-UHFFFAOYSA-N Tolbutamide Chemical compound CCCCNC(=O)NS(=O)(=O)C1=CC=C(C)C=C1 JLRGJRBPOGGCBT-UHFFFAOYSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- FNYLWPVRPXGIIP-UHFFFAOYSA-N Triamterene Chemical compound NC1=NC2=NC(N)=NC(N)=C2N=C1C1=CC=CC=C1 FNYLWPVRPXGIIP-UHFFFAOYSA-N 0.000 description 1
- 108010021006 Tyrothricin Proteins 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- MKFFGUZYVNDHIH-UHFFFAOYSA-N [2-(3,5-dihydroxyphenyl)-2-hydroxyethyl]-propan-2-ylazanium;sulfate Chemical compound OS(O)(=O)=O.CC(C)NCC(O)C1=CC(O)=CC(O)=C1.CC(C)NCC(O)C1=CC(O)=CC(O)=C1 MKFFGUZYVNDHIH-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 238000005273 aeration Methods 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 238000005054 agglomeration Methods 0.000 description 1
- NDAUXUAQIAJITI-UHFFFAOYSA-N albuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-UHFFFAOYSA-N 0.000 description 1
- 229940062527 alendronate Drugs 0.000 description 1
- OFCNXPDARWKPPY-UHFFFAOYSA-N allopurinol Chemical compound OC1=NC=NC2=C1C=NN2 OFCNXPDARWKPPY-UHFFFAOYSA-N 0.000 description 1
- 229960003459 allopurinol Drugs 0.000 description 1
- 229940087168 alpha tocopherol Drugs 0.000 description 1
- 108090000637 alpha-Amylases Proteins 0.000 description 1
- 102000004139 alpha-Amylases Human genes 0.000 description 1
- 229940024171 alpha-amylase Drugs 0.000 description 1
- AKNNEGZIBPJZJG-UHFFFAOYSA-N alpha-noscapine Natural products CN1CCC2=CC=3OCOC=3C(OC)=C2C1C1C2=CC=C(OC)C(OC)=C2C(=O)O1 AKNNEGZIBPJZJG-UHFFFAOYSA-N 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 229940024545 aluminum hydroxide Drugs 0.000 description 1
- 229960002684 aminocaproic acid Drugs 0.000 description 1
- 229960003556 aminophylline Drugs 0.000 description 1
- FQPFAHBPWDRTLU-UHFFFAOYSA-N aminophylline Chemical compound NCCN.O=C1N(C)C(=O)N(C)C2=C1NC=N2.O=C1N(C)C(=O)N(C)C2=C1NC=N2 FQPFAHBPWDRTLU-UHFFFAOYSA-N 0.000 description 1
- KRMDCWKBEZIMAB-UHFFFAOYSA-N amitriptyline Chemical compound C1CC2=CC=CC=C2C(=CCCN(C)C)C2=CC=CC=C21 KRMDCWKBEZIMAB-UHFFFAOYSA-N 0.000 description 1
- 229960003022 amoxicillin Drugs 0.000 description 1
- LSQZJLSUYDQPKJ-NJBDSQKTSA-N amoxicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=C(O)C=C1 LSQZJLSUYDQPKJ-NJBDSQKTSA-N 0.000 description 1
- 229940008238 amphetamine sulfate Drugs 0.000 description 1
- PYHRZPFZZDCOPH-UHFFFAOYSA-N amphetamine sulfate Chemical compound OS(O)(=O)=O.CC(N)CC1=CC=CC=C1.CC(N)CC1=CC=CC=C1 PYHRZPFZZDCOPH-UHFFFAOYSA-N 0.000 description 1
- 230000001195 anabolic effect Effects 0.000 description 1
- 230000003288 anthiarrhythmic effect Effects 0.000 description 1
- 239000004004 anti-anginal agent Substances 0.000 description 1
- 230000001773 anti-convulsant effect Effects 0.000 description 1
- 230000001142 anti-diarrhea Effects 0.000 description 1
- 230000003474 anti-emetic effect Effects 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 230000003561 anti-manic effect Effects 0.000 description 1
- 239000000883 anti-obesity agent Substances 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 230000002921 anti-spasmodic effect Effects 0.000 description 1
- 239000003416 antiarrhythmic agent Substances 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 229940125681 anticonvulsant agent Drugs 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 239000003793 antidiarrheal agent Substances 0.000 description 1
- 239000002111 antiemetic agent Substances 0.000 description 1
- 229940125683 antiemetic agent Drugs 0.000 description 1
- 229940125715 antihistaminic agent Drugs 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940127088 antihypertensive drug Drugs 0.000 description 1
- 229960005475 antiinfective agent Drugs 0.000 description 1
- 239000000228 antimanic agent Substances 0.000 description 1
- 239000002579 antinauseant Substances 0.000 description 1
- 229940127248 antinauseant drug Drugs 0.000 description 1
- 239000002221 antipyretic Substances 0.000 description 1
- 229940125716 antipyretic agent Drugs 0.000 description 1
- 229940064004 antiseptic throat preparations Drugs 0.000 description 1
- 229940124575 antispasmodic agent Drugs 0.000 description 1
- 229940127217 antithrombotic drug Drugs 0.000 description 1
- 229940043671 antithyroid preparations Drugs 0.000 description 1
- 239000002830 appetite depressant Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000000305 astragalus gummifer gum Substances 0.000 description 1
- 208000029618 autoimmune pulmonary alveolar proteinosis Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229960001335 benserazide hydrochloride Drugs 0.000 description 1
- 108010019077 beta-Amylase Proteins 0.000 description 1
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 1
- 229960000503 bisacodyl Drugs 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000008416 bone turnover Effects 0.000 description 1
- 229960004895 bretylium tosylate Drugs 0.000 description 1
- KVWNWTZZBKCOPM-UHFFFAOYSA-M bretylium tosylate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1.CC[N+](C)(C)CC1=CC=CC=C1Br KVWNWTZZBKCOPM-UHFFFAOYSA-M 0.000 description 1
- LHMHCLYDBQOYTO-UHFFFAOYSA-N bromofluoromethane Chemical compound FCBr LHMHCLYDBQOYTO-UHFFFAOYSA-N 0.000 description 1
- 229960000725 brompheniramine Drugs 0.000 description 1
- ZDIGNSYAACHWNL-UHFFFAOYSA-N brompheniramine Chemical compound C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Br)C=C1 ZDIGNSYAACHWNL-UHFFFAOYSA-N 0.000 description 1
- 239000000168 bronchodilator agent Substances 0.000 description 1
- RMRJXGBAOAMLHD-IHFGGWKQSA-N buprenorphine Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]11CC[C@]3([C@H](C1)[C@](C)(O)C(C)(C)C)OC)CN2CC1CC1 RMRJXGBAOAMLHD-IHFGGWKQSA-N 0.000 description 1
- 229960001736 buprenorphine Drugs 0.000 description 1
- GMTYREVWZXJPLF-AFHUBHILSA-N butorphanol D-tartrate Chemical compound OC(=O)[C@@H](O)[C@H](O)C(O)=O.N1([C@@H]2CC3=CC=C(C=C3[C@@]3([C@]2(CCCC3)O)CC1)O)CC1CCC1 GMTYREVWZXJPLF-AFHUBHILSA-N 0.000 description 1
- 229960001590 butorphanol tartrate Drugs 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000004227 calcium gluconate Substances 0.000 description 1
- 229960004494 calcium gluconate Drugs 0.000 description 1
- 235000013927 calcium gluconate Nutrition 0.000 description 1
- NEEHYRZPVYRGPP-UHFFFAOYSA-L calcium;2,3,4,5,6-pentahydroxyhexanoate Chemical compound [Ca+2].OCC(O)C(O)C(O)C(O)C([O-])=O.OCC(O)C(O)C(O)C(O)C([O-])=O NEEHYRZPVYRGPP-UHFFFAOYSA-L 0.000 description 1
- FAKRSMQSSFJEIM-RQJHMYQMSA-N captopril Chemical compound SC[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O FAKRSMQSSFJEIM-RQJHMYQMSA-N 0.000 description 1
- 229960000830 captopril Drugs 0.000 description 1
- 229960004399 carbocisteine Drugs 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- OCHFNTLZOZPXFE-JEDNCBNOSA-N carbonic acid;(2s)-2,6-diaminohexanoic acid Chemical compound OC(O)=O.NCCCC[C@H](N)C(O)=O OCHFNTLZOZPXFE-JEDNCBNOSA-N 0.000 description 1
- 229940083181 centrally acting adntiadrenergic agent methyldopa Drugs 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 229960001927 cetylpyridinium chloride Drugs 0.000 description 1
- YMKDRGPMQRFJGP-UHFFFAOYSA-M cetylpyridinium chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCC[N+]1=CC=CC=C1 YMKDRGPMQRFJGP-UHFFFAOYSA-M 0.000 description 1
- PBKVEOSEPXMKDN-LZHUFOCISA-N chembl2311030 Chemical compound CS(O)(=O)=O.CS(O)(=O)=O.CS(O)(=O)=O.CS(O)(=O)=O.C1=CC([C@H]2C[C@H](CN(C)[C@@H]2C2)C(=O)N[C@]3(C(=O)N4[C@H](C(N5CCC[C@H]5[C@]4(O)O3)=O)C(C)C)C(C)C)=C3C2=CNC3=C1.C1=CC([C@H]2C[C@H](CN(C)[C@@H]2C2)C(=O)N[C@]3(C(=O)N4[C@H](C(N5CCC[C@H]5[C@]4(O)O3)=O)C(C)CC)C(C)C)=C3C2=CNC3=C1.C1=CC([C@H]2C[C@H](CN(C)[C@@H]2C2)C(=O)N[C@]3(C(=O)N4[C@H](C(N5CCC[C@H]5[C@]4(O)O3)=O)CC(C)C)C(C)C)=C3C2=CNC3=C1.C([C@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@](C(N21)=O)(NC(=O)[C@H]1CN(C)[C@H]2[C@@H](C=3C=CC=C4NC=C(C=34)C2)C1)C(C)C)C1=CC=CC=C1 PBKVEOSEPXMKDN-LZHUFOCISA-N 0.000 description 1
- XMEVHPAGJVLHIG-FMZCEJRJSA-N chembl454950 Chemical compound [Cl-].C1=CC=C2[C@](O)(C)[C@H]3C[C@H]4[C@H]([NH+](C)C)C(O)=C(C(N)=O)C(=O)[C@@]4(O)C(O)=C3C(=O)C2=C1O XMEVHPAGJVLHIG-FMZCEJRJSA-N 0.000 description 1
- 230000001055 chewing effect Effects 0.000 description 1
- 229960003260 chlorhexidine Drugs 0.000 description 1
- ZPEIMTDSQAKGNT-UHFFFAOYSA-N chlorpromazine Chemical compound C1=C(Cl)C=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 ZPEIMTDSQAKGNT-UHFFFAOYSA-N 0.000 description 1
- 229960001076 chlorpromazine Drugs 0.000 description 1
- 229960001523 chlortalidone Drugs 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 229960001380 cimetidine Drugs 0.000 description 1
- CCGSUNCLSOWKJO-UHFFFAOYSA-N cimetidine Chemical compound N#CNC(=N/C)\NCCSCC1=NC=N[C]1C CCGSUNCLSOWKJO-UHFFFAOYSA-N 0.000 description 1
- ACSIXWWBWUQEHA-UHFFFAOYSA-N clodronic acid Chemical compound OP(O)(=O)C(Cl)(Cl)P(O)(O)=O ACSIXWWBWUQEHA-UHFFFAOYSA-N 0.000 description 1
- 229960002286 clodronic acid Drugs 0.000 description 1
- 229960004415 codeine phosphate Drugs 0.000 description 1
- 229960003871 codeine sulfate Drugs 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- WZHCOOQXZCIUNC-UHFFFAOYSA-N cyclandelate Chemical compound C1C(C)(C)CC(C)CC1OC(=O)C(O)C1=CC=CC=C1 WZHCOOQXZCIUNC-UHFFFAOYSA-N 0.000 description 1
- 229960000729 cyclandelate Drugs 0.000 description 1
- 229960003710 dantrolene sodium Drugs 0.000 description 1
- LTWQNYPDAUSXBC-CDJGKPBYSA-L dantrolene sodium hemiheptahydrate Chemical compound O.O.O.O.O.O.O.[Na+].[Na+].C1=CC([N+](=O)[O-])=CC=C1C(O1)=CC=C1\C=N\N1C(=O)[N-]C(=O)C1.C1=CC([N+](=O)[O-])=CC=C1C(O1)=CC=C1\C=N\N1C(=O)[N-]C(=O)C1 LTWQNYPDAUSXBC-CDJGKPBYSA-L 0.000 description 1
- 229940124581 decongestants Drugs 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 229960003914 desipramine Drugs 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 229960001985 dextromethorphan Drugs 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- NIJJYAXOARWZEE-UHFFFAOYSA-N di-n-propyl-acetic acid Natural products CCCC(C(O)=O)CCC NIJJYAXOARWZEE-UHFFFAOYSA-N 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 229960002069 diamorphine Drugs 0.000 description 1
- AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 1
- 229960003529 diazepam Drugs 0.000 description 1
- ATKXDQOHNICLQW-UHFFFAOYSA-N dichloralphenazone Chemical compound OC(O)C(Cl)(Cl)Cl.OC(O)C(Cl)(Cl)Cl.CN1C(C)=CC(=O)N1C1=CC=CC=C1 ATKXDQOHNICLQW-UHFFFAOYSA-N 0.000 description 1
- 229960005422 dichloralphenazone Drugs 0.000 description 1
- CURUTKGFNZGFSE-UHFFFAOYSA-N dicyclomine Chemical compound C1CCCCC1C1(C(=O)OCCN(CC)CC)CCCCC1 CURUTKGFNZGFSE-UHFFFAOYSA-N 0.000 description 1
- 229960002777 dicycloverine Drugs 0.000 description 1
- 235000015872 dietary supplement Nutrition 0.000 description 1
- SSAJNPNVUYMUCI-UHFFFAOYSA-N diethyl-[2-[2-(naphthalen-1-ylmethyl)-3-(oxolan-2-yl)propanoyl]oxyethyl]azanium;2-hydroxy-2-oxoacetate Chemical compound OC(=O)C([O-])=O.C=1C=CC2=CC=CC=C2C=1CC(C(=O)OCC[NH+](CC)CC)CC1CCCO1 SSAJNPNVUYMUCI-UHFFFAOYSA-N 0.000 description 1
- 229960004166 diltiazem Drugs 0.000 description 1
- HSUGRBWQSSZJOP-RTWAWAEBSA-N diltiazem Chemical compound C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CCN(C)C)C2=CC=CC=C2S1 HSUGRBWQSSZJOP-RTWAWAEBSA-N 0.000 description 1
- 235000019329 dioctyl sodium sulphosuccinate Nutrition 0.000 description 1
- 229960000520 diphenhydramine Drugs 0.000 description 1
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical compound C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 1
- 229960004192 diphenoxylate Drugs 0.000 description 1
- HYPPXZBJBPSRLK-UHFFFAOYSA-N diphenoxylate Chemical compound C1CC(C(=O)OCC)(C=2C=CC=CC=2)CCN1CCC(C#N)(C=1C=CC=CC=1)C1=CC=CC=C1 HYPPXZBJBPSRLK-UHFFFAOYSA-N 0.000 description 1
- 229960000879 diphenylpyraline Drugs 0.000 description 1
- OWQUZNMMYNAXSL-UHFFFAOYSA-N diphenylpyraline Chemical compound C1CN(C)CCC1OC(C=1C=CC=CC=1)C1=CC=CC=C1 OWQUZNMMYNAXSL-UHFFFAOYSA-N 0.000 description 1
- 238000002845 discoloration Methods 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 229960001066 disopyramide Drugs 0.000 description 1
- UVTNFZQICZKOEM-UHFFFAOYSA-N disopyramide Chemical compound C=1C=CC=NC=1C(C(N)=O)(CCN(C(C)C)C(C)C)C1=CC=CC=C1 UVTNFZQICZKOEM-UHFFFAOYSA-N 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- 230000001882 diuretic effect Effects 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- RXPRRQLKFXBCSJ-UHFFFAOYSA-N dl-Vincamin Natural products C1=CC=C2C(CCN3CCC4)=C5C3C4(CC)CC(O)(C(=O)OC)N5C2=C1 RXPRRQLKFXBCSJ-UHFFFAOYSA-N 0.000 description 1
- DLNKOYKMWOXYQA-UHFFFAOYSA-N dl-pseudophenylpropanolamine Natural products CC(N)C(O)C1=CC=CC=C1 DLNKOYKMWOXYQA-UHFFFAOYSA-N 0.000 description 1
- 229940020465 domperidone 10 mg Drugs 0.000 description 1
- 229960005426 doxepin Drugs 0.000 description 1
- ODQWQRRAPPTVAG-GZTJUZNOSA-N doxepin Chemical compound C1OC2=CC=CC=C2C(=C/CCN(C)C)/C2=CC=CC=C21 ODQWQRRAPPTVAG-GZTJUZNOSA-N 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 229960002179 ephedrine Drugs 0.000 description 1
- 229960005139 epinephrine Drugs 0.000 description 1
- OFKDAAIKGIBASY-VFGNJEKYSA-N ergotamine Chemical compound C([C@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@@](C(N21)=O)(C)NC(=O)[C@H]1CN([C@H]2C(C3=CC=CC4=NC=C([C]34)C2)=C1)C)C1=CC=CC=C1 OFKDAAIKGIBASY-VFGNJEKYSA-N 0.000 description 1
- 229960004943 ergotamine Drugs 0.000 description 1
- XCGSFFUVFURLIX-UHFFFAOYSA-N ergotaminine Natural products C1=C(C=2C=CC=C3NC=C(C=23)C2)C2N(C)CC1C(=O)NC(C(N12)=O)(C)OC1(O)C1CCCN1C(=O)C2CC1=CC=CC=C1 XCGSFFUVFURLIX-UHFFFAOYSA-N 0.000 description 1
- 229960004142 erythromycin stearate Drugs 0.000 description 1
- 230000000913 erythropoietic effect Effects 0.000 description 1
- 210000003238 esophagus Anatomy 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 229940009626 etidronate Drugs 0.000 description 1
- 229940066493 expectorants Drugs 0.000 description 1
- 229960001877 fenfluramine hydrochloride Drugs 0.000 description 1
- 239000011790 ferrous sulphate Substances 0.000 description 1
- 235000003891 ferrous sulphate Nutrition 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 229960004273 floxacillin Drugs 0.000 description 1
- PARMJFIQRZRMHG-VICXVTCVSA-M flucloxacillin sodium monohydrate Chemical compound O.[Na+].N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C([O-])=O)=O)C(=O)C1=C(C)ON=C1C1=C(F)C=CC=C1Cl PARMJFIQRZRMHG-VICXVTCVSA-M 0.000 description 1
- 229960002690 fluphenazine Drugs 0.000 description 1
- 229960003528 flurazepam Drugs 0.000 description 1
- SAADBVWGJQAEFS-UHFFFAOYSA-N flurazepam Chemical compound N=1CC(=O)N(CCN(CC)CC)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1F SAADBVWGJQAEFS-UHFFFAOYSA-N 0.000 description 1
- 229960002390 flurbiprofen Drugs 0.000 description 1
- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 description 1
- 239000011724 folic acid Substances 0.000 description 1
- 229960000304 folic acid Drugs 0.000 description 1
- 235000019152 folic acid Nutrition 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 229960003883 furosemide Drugs 0.000 description 1
- 230000006589 gland dysfunction Effects 0.000 description 1
- MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 description 1
- 229960004666 glucagon Drugs 0.000 description 1
- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- FETSQPAGYOVAQU-UHFFFAOYSA-N glyceryl palmitostearate Chemical compound OCC(O)CO.CCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O FETSQPAGYOVAQU-UHFFFAOYSA-N 0.000 description 1
- 229940046813 glyceryl palmitostearate Drugs 0.000 description 1
- 229960003711 glyceryl trinitrate Drugs 0.000 description 1
- 238000011194 good manufacturing practice Methods 0.000 description 1
- 229960002146 guaifenesin Drugs 0.000 description 1
- YUFWAVFNITUSHI-UHFFFAOYSA-N guanethidine monosulfate Chemical compound [H+].[H+].[O-]S([O-])(=O)=O.NC(=N)NCCN1CCCCCCC1 YUFWAVFNITUSHI-UHFFFAOYSA-N 0.000 description 1
- 230000003394 haemopoietic effect Effects 0.000 description 1
- 229960003878 haloperidol Drugs 0.000 description 1
- UXNFIJPHRQEWRQ-UHFFFAOYSA-N hexamethylenetetramine mandelate salt Chemical compound C1N(C2)CN3CN1CN2C3.OC(=O)C(O)C1=CC=CC=C1 UXNFIJPHRQEWRQ-UHFFFAOYSA-N 0.000 description 1
- 235000019534 high fructose corn syrup Nutrition 0.000 description 1
- 229960002474 hydralazine Drugs 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 229960002003 hydrochlorothiazide Drugs 0.000 description 1
- 230000003345 hyperglycaemic effect Effects 0.000 description 1
- 239000003326 hypnotic agent Substances 0.000 description 1
- 229940126904 hypoglycaemic agent Drugs 0.000 description 1
- 229960004801 imipramine Drugs 0.000 description 1
- BCGWQEUPMDMJNV-UHFFFAOYSA-N imipramine Chemical compound C1CC2=CC=CC=C2N(CCCN(C)C)C2=CC=CC=C21 BCGWQEUPMDMJNV-UHFFFAOYSA-N 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 229940039009 isoproterenol Drugs 0.000 description 1
- MOYKHGMNXAOIAT-JGWLITMVSA-N isosorbide dinitrate Chemical compound [O-][N+](=O)O[C@H]1CO[C@@H]2[C@H](O[N+](=O)[O-])CO[C@@H]21 MOYKHGMNXAOIAT-JGWLITMVSA-N 0.000 description 1
- 229960000201 isosorbide dinitrate Drugs 0.000 description 1
- 229940108371 lansoprazole 15 mg Drugs 0.000 description 1
- 229940125722 laxative agent Drugs 0.000 description 1
- 230000002475 laxative effect Effects 0.000 description 1
- 229960004502 levodopa Drugs 0.000 description 1
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 1
- 229910052808 lithium carbonate Inorganic materials 0.000 description 1
- 229940008015 lithium carbonate Drugs 0.000 description 1
- INHCSSUBVCNVSK-UHFFFAOYSA-L lithium sulfate Inorganic materials [Li+].[Li+].[O-]S([O-])(=O)=O INHCSSUBVCNVSK-UHFFFAOYSA-L 0.000 description 1
- 229940087748 lithium sulfate Drugs 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 229960005015 local anesthetics Drugs 0.000 description 1
- YQZBAXDVDZTKEQ-UHFFFAOYSA-N loxapine succinate Chemical compound [H+].[H+].[O-]C(=O)CCC([O-])=O.C1CN(C)CCN1C1=NC2=CC=CC=C2OC2=CC=C(Cl)C=C12 YQZBAXDVDZTKEQ-UHFFFAOYSA-N 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
- 235000014380 magnesium carbonate Nutrition 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 229960004992 maprotiline hydrochloride Drugs 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- HYYBABOKPJLUIN-UHFFFAOYSA-N mefenamic acid Chemical compound CC1=CC=CC(NC=2C(=CC=CC=2)C(O)=O)=C1C HYYBABOKPJLUIN-UHFFFAOYSA-N 0.000 description 1
- 229960003464 mefenamic acid Drugs 0.000 description 1
- 238000002074 melt spinning Methods 0.000 description 1
- 229960001344 methylphenidate Drugs 0.000 description 1
- 229960004503 metoclopramide Drugs 0.000 description 1
- TTWJBBZEZQICBI-UHFFFAOYSA-N metoclopramide Chemical compound CCN(CC)CCNC(=O)C1=CC(Cl)=C(N)C=C1OC TTWJBBZEZQICBI-UHFFFAOYSA-N 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 235000019426 modified starch Nutrition 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- 230000000510 mucolytic effect Effects 0.000 description 1
- 229960001132 naftidrofuryl Drugs 0.000 description 1
- 229960000805 nalbuphine Drugs 0.000 description 1
- NETZHAKZCGBWSS-CEDHKZHLSA-N nalbuphine Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]1(O)CC[C@@H]3O)CN2CC1CCC1 NETZHAKZCGBWSS-CEDHKZHLSA-N 0.000 description 1
- 229960000210 nalidixic acid Drugs 0.000 description 1
- MHWLWQUZZRMNGJ-UHFFFAOYSA-N nalidixic acid Chemical compound C1=C(C)N=C2N(CC)C=C(C(O)=O)C(=O)C2=C1 MHWLWQUZZRMNGJ-UHFFFAOYSA-N 0.000 description 1
- 229960002009 naproxen Drugs 0.000 description 1
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 1
- PLPRGLOFPNJOTN-UHFFFAOYSA-N narcotine Natural products COc1ccc2C(OC(=O)c2c1OC)C3Cc4c(CN3C)cc5OCOc5c4OC PLPRGLOFPNJOTN-UHFFFAOYSA-N 0.000 description 1
- 239000003176 neuroleptic agent Substances 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 description 1
- 229960001597 nifedipine Drugs 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
- 229960004708 noscapine Drugs 0.000 description 1
- 235000020939 nutritional additive Nutrition 0.000 description 1
- 229960000988 nystatin Drugs 0.000 description 1
- VQOXZBDYSJBXMA-NQTDYLQESA-N nystatin A1 Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/CC/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 VQOXZBDYSJBXMA-NQTDYLQESA-N 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- QUANRIQJNFHVEU-UHFFFAOYSA-N oxirane;propane-1,2,3-triol Chemical compound C1CO1.OCC(O)CO QUANRIQJNFHVEU-UHFFFAOYSA-N 0.000 description 1
- 229960001834 oxprenolol hydrochloride Drugs 0.000 description 1
- LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Natural products O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 0.000 description 1
- WRUUGTRCQOWXEG-UHFFFAOYSA-N pamidronate Chemical compound NCCC(O)(P(O)(O)=O)P(O)(O)=O WRUUGTRCQOWXEG-UHFFFAOYSA-N 0.000 description 1
- 229940046231 pamidronate Drugs 0.000 description 1
- 229960001789 papaverine Drugs 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000013618 particulate matter Substances 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 229960004321 pentaerithrityl tetranitrate Drugs 0.000 description 1
- OQGYMIIFOSJQSF-DTOXXUQYSA-N pentazocine hcl Chemical compound Cl.C1C2=CC=C(O)C=C2[C@@]2(C)[C@@H](C)[C@@H]1N(CC=C(C)C)CC2 OQGYMIIFOSJQSF-DTOXXUQYSA-N 0.000 description 1
- 229960003809 pentazocine hydrochloride Drugs 0.000 description 1
- 230000008447 perception Effects 0.000 description 1
- 239000000810 peripheral vasodilating agent Substances 0.000 description 1
- 229960002116 peripheral vasodilator Drugs 0.000 description 1
- 229960000482 pethidine Drugs 0.000 description 1
- 230000004526 pharmaceutical effect Effects 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 229960003562 phentermine Drugs 0.000 description 1
- 229960002895 phenylbutazone Drugs 0.000 description 1
- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 description 1
- DLNKOYKMWOXYQA-APPZFPTMSA-N phenylpropanolamine Chemical compound C[C@@H](N)[C@H](O)C1=CC=CC=C1 DLNKOYKMWOXYQA-APPZFPTMSA-N 0.000 description 1
- 229960000395 phenylpropanolamine Drugs 0.000 description 1
- 229960002790 phenytoin sodium Drugs 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 239000008389 polyethoxylated castor oil Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229940068965 polysorbates Drugs 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 239000008057 potassium phosphate buffer Substances 0.000 description 1
- 229960005205 prednisolone Drugs 0.000 description 1
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 229960003081 probenecid Drugs 0.000 description 1
- DBABZHXKTCFAPX-UHFFFAOYSA-N probenecid Chemical compound CCCN(CCC)S(=O)(=O)C1=CC=C(C(O)=O)C=C1 DBABZHXKTCFAPX-UHFFFAOYSA-N 0.000 description 1
- 229960000244 procainamide Drugs 0.000 description 1
- REQCZEXYDRLIBE-UHFFFAOYSA-N procainamide Chemical compound CCN(CC)CCNC(=O)C1=CC=C(N)C=C1 REQCZEXYDRLIBE-UHFFFAOYSA-N 0.000 description 1
- 238000004886 process control Methods 0.000 description 1
- 229960005439 propantheline bromide Drugs 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 229960004604 propranolol hydrochloride Drugs 0.000 description 1
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol hydrochloride Natural products C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 description 1
- 229960002662 propylthiouracil Drugs 0.000 description 1
- 229950008679 protamine sulfate Drugs 0.000 description 1
- 239000011253 protective coating Substances 0.000 description 1
- KWGRBVOPPLSCSI-WCBMZHEXSA-N pseudoephedrine Chemical compound CN[C@@H](C)[C@@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WCBMZHEXSA-N 0.000 description 1
- 229960003908 pseudoephedrine Drugs 0.000 description 1
- 229940001470 psychoactive drug Drugs 0.000 description 1
- 239000004089 psychotropic agent Substances 0.000 description 1
- 230000000506 psychotropic effect Effects 0.000 description 1
- 235000008160 pyridoxine Nutrition 0.000 description 1
- 239000011677 pyridoxine Substances 0.000 description 1
- XHKUDCCTVQUHJQ-LCYSNFERSA-N quinidine D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O.C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@H]2[C@@H](O)C1=CC=NC2=CC=C(OC)C=C21 XHKUDCCTVQUHJQ-LCYSNFERSA-N 0.000 description 1
- 229960002454 quinidine gluconate Drugs 0.000 description 1
- 229960004482 quinidine sulfate Drugs 0.000 description 1
- 229940048832 ranitidine 150 mg Drugs 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 230000033764 rhythmic process Effects 0.000 description 1
- IOVGROKTTNBUGK-SJCJKPOMSA-N ritodrine Chemical compound N([C@@H](C)[C@H](O)C=1C=CC(O)=CC=1)CCC1=CC=C(O)C=C1 IOVGROKTTNBUGK-SJCJKPOMSA-N 0.000 description 1
- 229960001634 ritodrine Drugs 0.000 description 1
- 229960002052 salbutamol Drugs 0.000 description 1
- 208000026451 salivation Diseases 0.000 description 1
- STECJAGHUSJQJN-FWXGHANASA-N scopolamine Chemical compound C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-FWXGHANASA-N 0.000 description 1
- 229960002646 scopolamine Drugs 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- FHHPUSMSKHSNKW-SMOYURAASA-M sodium deoxycholate Chemical compound [Na+].C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC([O-])=O)C)[C@@]2(C)[C@@H](O)C1 FHHPUSMSKHSNKW-SMOYURAASA-M 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229910000031 sodium sesquicarbonate Inorganic materials 0.000 description 1
- 235000018341 sodium sesquicarbonate Nutrition 0.000 description 1
- 229940084026 sodium valproate Drugs 0.000 description 1
- AEQFSUDEHCCHBT-UHFFFAOYSA-M sodium valproate Chemical compound [Na+].CCCC(C([O-])=O)CCC AEQFSUDEHCCHBT-UHFFFAOYSA-M 0.000 description 1
- FJPYVLNWWICYDW-UHFFFAOYSA-M sodium;5,5-diphenylimidazolidin-1-ide-2,4-dione Chemical compound [Na+].O=C1[N-]C(=O)NC1(C=1C=CC=CC=1)C1=CC=CC=C1 FJPYVLNWWICYDW-UHFFFAOYSA-M 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-N sodium;dodecyl sulfate;hydron Chemical compound [H+].[Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-N 0.000 description 1
- LXMSZDCAJNLERA-ZHYRCANASA-N spironolactone Chemical compound C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)SC(=O)C)C[C@@]21CCC(=O)O1 LXMSZDCAJNLERA-ZHYRCANASA-N 0.000 description 1
- 229960002256 spironolactone Drugs 0.000 description 1
- 235000003702 sterols Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000000859 sublimation Methods 0.000 description 1
- 230000008022 sublimation Effects 0.000 description 1
- 229960003329 sulfinpyrazone Drugs 0.000 description 1
- MBGGBVCUIVRRBF-UHFFFAOYSA-N sulfinpyrazone Chemical compound O=C1N(C=2C=CC=CC=2)N(C=2C=CC=CC=2)C(=O)C1CCS(=O)C1=CC=CC=C1 MBGGBVCUIVRRBF-UHFFFAOYSA-N 0.000 description 1
- 229940005127 sumatriptan 50 mg Drugs 0.000 description 1
- 235000019605 sweet taste sensations Nutrition 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229960003188 temazepam Drugs 0.000 description 1
- KFVSLSTULZVNPG-UHFFFAOYSA-N terbutaline sulfate Chemical compound [O-]S([O-])(=O)=O.CC(C)(C)[NH2+]CC(O)C1=CC(O)=CC(O)=C1.CC(C)(C)[NH2+]CC(O)C1=CC(O)=CC(O)=C1 KFVSLSTULZVNPG-UHFFFAOYSA-N 0.000 description 1
- RBTVSNLYYIMMKS-UHFFFAOYSA-N tert-butyl 3-aminoazetidine-1-carboxylate;hydrochloride Chemical compound Cl.CC(C)(C)OC(=O)N1CC(N)C1 RBTVSNLYYIMMKS-UHFFFAOYSA-N 0.000 description 1
- IJAAJNPGRSCJKT-UHFFFAOYSA-N tetraaluminum;trisilicate Chemical compound [Al+3].[Al+3].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-].[O-][Si]([O-])([O-])[O-].[O-][Si]([O-])([O-])[O-] IJAAJNPGRSCJKT-UHFFFAOYSA-N 0.000 description 1
- 229960004989 tetracycline hydrochloride Drugs 0.000 description 1
- 229960000278 theophylline Drugs 0.000 description 1
- 239000011721 thiamine Substances 0.000 description 1
- 235000019157 thiamine Nutrition 0.000 description 1
- KYMBYSLLVAOCFI-UHFFFAOYSA-N thiamine Chemical compound CC1=C(CCO)SCN1CC1=CN=C(C)N=C1N KYMBYSLLVAOCFI-UHFFFAOYSA-N 0.000 description 1
- 229960003495 thiamine Drugs 0.000 description 1
- 229960002784 thioridazine Drugs 0.000 description 1
- 229940043672 thyroid preparations Drugs 0.000 description 1
- 229940034208 thyroxine Drugs 0.000 description 1
- XUIIKFGFIJCVMT-UHFFFAOYSA-N thyroxine-binding globulin Natural products IC1=CC(CC([NH3+])C([O-])=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-UHFFFAOYSA-N 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- 229960005371 tolbutamide Drugs 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 229960001288 triamterene Drugs 0.000 description 1
- ZEWQUBUPAILYHI-UHFFFAOYSA-N trifluoperazine Chemical compound C1CN(C)CCN1CCCN1C2=CC(C(F)(F)F)=CC=C2SC2=CC=CC=C21 ZEWQUBUPAILYHI-UHFFFAOYSA-N 0.000 description 1
- 229960002324 trifluoperazine Drugs 0.000 description 1
- 229940035722 triiodothyronine Drugs 0.000 description 1
- WCTAGTRAWPDFQO-UHFFFAOYSA-K trisodium;hydrogen carbonate;carbonate Chemical compound [Na+].[Na+].[Na+].OC([O-])=O.[O-]C([O-])=O WCTAGTRAWPDFQO-UHFFFAOYSA-K 0.000 description 1
- GSXRBRIWJGAPDU-BBVRJQLQSA-N tyrocidine A Chemical compound C([C@H]1C(=O)N[C@H](C(=O)N[C@@H](CCCN)C(=O)N[C@H](C(N[C@H](CC=2C=CC=CC=2)C(=O)N2CCC[C@H]2C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N1)=O)CC(C)C)C(C)C)C1=CC=C(O)C=C1 GSXRBRIWJGAPDU-BBVRJQLQSA-N 0.000 description 1
- 229960003281 tyrothricin Drugs 0.000 description 1
- 230000003424 uricosuric effect Effects 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 239000005526 vasoconstrictor agent Substances 0.000 description 1
- 229960001722 verapamil Drugs 0.000 description 1
- 229960002726 vincamine Drugs 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 229940011671 vitamin b6 Drugs 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
Classifications
-
- 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
- A61J7/00—Devices for administering medicines orally, e.g. spoons; Pill counting devices; Arrangements for time indication or reminder for taking medicine
- A61J7/0015—Devices specially adapted for taking medicines
- A61J7/0061—Swallow helping devices, e.g. tongue shields
-
- 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
- A61J7/00—Devices for administering medicines orally, e.g. spoons; Pill counting devices; Arrangements for time indication or reminder for taking medicine
- A61J7/0076—Medicament distribution means
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
-
- 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
- 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
- A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
- A61J1/03—Containers specially adapted for medical or pharmaceutical purposes for pills or tablets
-
- 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
- A61J3/005—Coating of tablets or the like
-
- 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
- A61K9/0007—Effervescent
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
- A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
-
- 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
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
- A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
-
- 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
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
- A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
Definitions
- the present is directed to fast melt multiparticulate formulations for oral use.
- the multiparticulates can be used in a multiple dose delivery device which dispenses a unit dose of the powder upon actuation, or can be packaged for dispensation in sachets or like unit dose containers.
- Achlorhydria is a condition wherein there is an abnormal deficiency or absence of free hydrochloric acid in the gastric secretions of the stomach. This condition hinders the disintegration and/or dissolution of oral solid dosage forms, particularly dosage forms with high or insoluble excipient payloads.
- the present dosage form is in fast melt multiparticulate form, it does not need to undergo disintegration and/or dissolution to the same extent as solid dosage forms
- Fast melt drug formulations have also been developed to facilitate the oral administration of oral agents to patients normally having difficulty ingesting conventional solid oral dosage forms.
- Fast melt formulations are typically in the form of tablets or lozenges that dissolve or disperse in a patient's mouth within a minute without the need of water or chewing.
- Drug delivery formulations which exhibit fast melt properties can improve patient compliance due to the ease of swallowing as well as the absence of a need for the co-administration of water or another fluid.
- fast melt systems can be formulated as to have a superior taste and improved accuracy of dosing as compared to liquid preparations.
- a drug formulation for gastrointestinal deposition comprising a free flowing plurality of particles comprising an active agent and a water-soluble excipient, wherein the particles have a mean diameter of greater than about 10 ⁇ m to about 1 mm, and the formulation is capable of dissolving or dispersing in a patient's mouth within 1 minute after administration without the co-administration of a fluid.
- the present invention in its first aspect, provides a formulation which exhibits the benefits of fast melt formulations as well as the benefits of multiparticulate formulations. It also facilitates the delivery of a wide range of therapeutic agents for gastrointestinal deposition and minimizes pulmonary deposition of materials having undesirable or unknown pulmonary toxicology but which are approved for oral delivery.
- the formulation can contain minimal excipient and be used in a multiple dose delivery device which dispenses a unit dose of the formulation upon actuation. Such delivery devices are disclosed in WO 01/64182.
- the present invention provides a drug formulation for gastrointestinal deposition, said formulation comprising a free flowing plurality of particles and including an active agent and a water-soluble excipient, wherein the particles have a mean diameter of greater than about 10 ⁇ m to about 1 mm, and the excipient has a negative heat of solution.
- a significant advantage of formulations in accordance with the second aspect of the invention is that, when administered via the oral cavity, the local cooling caused by the water-soluble excipient dissolving in saliva serves to mask the taste of the active agent in a manner which does not delay the release, or dissolution of the active agent itself.
- formulations in accordance with the second aspect of the invention are capable of dissolving or dispersing in a patient's mouth within one minute after administration, without the co-administration of a fluid.
- Such preferred formulations are also examples of the first aspect of the invention and will provide all of the aforementioned benefits associated with the first aspect of the invention.
- Drug formulations in accordance with either the first or the second aspect of the invention are preferably arranged for direct, un-encapsulated administration to a patient's oral cavity. It is also preferred for the particles to be non-compressed.
- the particles each include both active agent and water-soluble excipient.
- the particles can comprise a core and a coating, with the coating including a quantity of the water-soluble excipient.
- the particles are formed by melt-coating core particles with a coating material that includes (and may consist of) a quantity of the excipient, at a temperature below that at which the active agent melts or decomposes.
- a coating material that includes (and may consist of) a quantity of the excipient, at a temperature below that at which the active agent melts or decomposes.
- Forming the particles in this manner is considered to provide them with surface properties that render them easily wetted and capable of rapidly absorbing water from their environment and, thus, able to facilitate the rapid dissolution or dispersion of the formulation, especially the active agent, when the formulation is exposed to an aqueous environment, such as in the oral cavity.
- a quantity of the active agent can be included in the core or core particles and/or in the coating or coating material.
- the coating or coating material is substantially free of active agent, whereas in others, the core is substantially free of active agent.
- the coating or coating material comprises a water-soluble or hydrophilic binder.
- the binder melts or softens sufficiently to melt-coat the core particles at a temperature below that at which the active agent melts or decomposes.
- the water-soluble excipient melts or softens sufficiently to melt-coat the core particles at a temperature below that at which the active agent melts or decomposes.
- the binder melts or softens sufficiently to melt-coat the core particles at a temperature below that at which the water-soluble excipient melts or decomposes.
- the coating or coating material substantially completely covers the surface of the core or core particles.
- particles in accordance with the present invention can comprise a core that consists substantially or entirely of active agent surrounded by a coating that comprises water-soluble excipient either alone, or in combination with a water-soluble or hydrophilic binder.
- a coating that comprises water-soluble excipient either alone, or in combination with a water-soluble or hydrophilic binder.
- the water-soluble excipient is employed alone in such particles, it is preferred for it to be capable of melting or softening sufficiently to melt-coat the core particles at a temperature below that at which the active agent melts or decomposes.
- the water-soluble excipient need not be capable of melting or softening at a temperature below the melting or decomposition temperature of the active agent.
- the binder should be capable both of melting or softening sufficiently to melt-coat the core particles at a temperature below that at which the active agent melts or decomposes, and of binding the water-soluble excipient in the coating.
- the core or core particles in addition to including active agent, can also include a quantity of the water-soluble excipient and/or an additional excipient, which may also be water soluble, but which does not necessarily qualify as a water-soluble excipient in accordance with the present invention.
- the core can comprise a granulation of such an additional excipient (e.g. polyvinyl alcohol, or polyvinylpyrrolidine) and active agent, or consist of a particle (e.g. a microcrystalline cellulose sphere) of additional excipient coated with active agent.
- the core can consist entirely of water-soluble excipient.
- the coat or coating material comprises active agent and either an additional quantity of water-soluble excipient, or a binder.
- additional water-soluble excipient can also be present in therein.
- formulations in accordance with either aspect of the present invention are formed by a process in which the active agent is not raised to or above its melting point, or a temperature at which a significant proportion thereof is caused to decompose.
- the melting point of the water-soluble excipient is preferably equal to or below 150, 120 or 110° C., and is preferably at least 40 or 50° C.
- the excipient melts at around or below 100° C.
- the melting point of the binder, if employed, is preferably equal to or below 150, 120 or 110° C., and is preferably at least 40 or 50° C.
- the binder melts at around or below 100° C. In certain embodiments, the melting point of the excipient exceeds that of the binder.
- the water-soluble excipient preferably, has a heat of solution equal to or below ⁇ 7 KCal/Kg. More preferably, the heat of solution of the water-soluble excipient is equal to or below ⁇ 10, ⁇ 15, ⁇ 20, ⁇ 25, or ⁇ 30 KCal/Kg.
- the solubility in water of the water-soluble excipient is preferably at least 20, 30 or 40% w/w at 25° C.
- the water-soluble excipient is preferably a sugar, sugar alcohol, polyethylene glycol (PEG), or polyethylene oxide, and is preferably not lactose. Formulations in accordance with the invention, preferably, are lactose free.
- the preferred water-soluble excipients are the sugar alcohols including, but not limited to sorbitol, mannitol, maltitol, reduced starch saccharide, xylitol, reduced paratinose, erythritol, and combinations thereof.
- the preferred sugar is glucose.
- Other suitable water-soluble excipients include gelatin, partially hydrolyzed gelatin, hydrolyzed dextran, dextrin, alginate and mixtures thereof.
- Preferred binders include polyethylene glycols (PEG) and polyethylene oxides.
- the core or core particles include an additional excipient for controlling or delaying the release of the active agent.
- the core or core particles can include a layer or coating of such an additional excipient encapsulating an inner core comprising the active agent.
- the additional excipient can be selected from those known to persons skilled in the art to be capable of controlling the release of an encapsulated active agent.
- excipients include those commonly used to provide enteric and sustained release coatings. Examples of the former include cellulose acetate phthalate, hydroxypropyl-methylcelluose phthalate, polymethacrylates, such as Eudragit® L 100-55 or L 30 D-55, and Shellac. Examples of the latter include ethylcellulose, hydroxypropyl-celluose, hydroxypropylmethylcelluose, and polymethacrylates, such as Eudragit® RL and RS film-coating systems.
- formulations in accordance with the invention can provide rapid release of the active agent.
- rapid release should be understood to mean that such formulations release at least 80% of their active agent within 45 minutes in standard dissolution tests.
- such formulations typically release at least 80% of their active agent within 40, 30, 20, 15 and preferably 10 minutes after being administered to a patient's oral cavity.
- more soluble active agents such formulations typically release at least 80% of their active agent within 10, 7 and preferably 5 minutes after being administered to a patient's oral cavity.
- the active agent will dissolve into an aqueous environment more rapidly from a formulation in accordance with the invention than it would if it had not been incorporated in such a formulation.
- the present invention provides a method of preparing a drug formulation in accordance with the first or second aspect of the invention, comprising forming the particles by melt-coating core particles with a coating material that includes a quantity of the water-soluble excipient, at a temperature below the melting point or decomposition temperature of the active agent.
- the invention provides the use of a drug formulation in accordance with the first or second aspect of the invention, or a drug formulation prepared by a method in accordance with the third aspect of the invention, for the preparation of a medicament for treating a human or animal patient, wherein the formulation is administered directly and in an un-encapsulated form to the patient's oral cavity.
- the invention also provides a method of treating a human or animal patient, wherein a formulation in accordance with the first or second aspect of the invention, or prepared by a method in accordance with a third aspect of the invention, is administered in a un-encapsulated form directly into the patient's oral cavity.
- formulations in accordance with either the first aspect or the second aspect of the invention may include additional particles with different properties to those described above.
- the additional particles may not include any active agent.
- Certain embodiments of the invention comprise a fast melt multiparticulate formulation which contains a salivary stimulant to facilitate hydration of the formulation and the swallowing of a unit dose of the multiparticulates upon oral delivery.
- Certain embodiments of the invention comprise a fast melt multiparticulate formulation which has a desired particle range in order to minimize pulmonary aspiration of particles.
- Fast melt multiparticulate formulations in accordance with the invention are, preferably, divisable into unit doses (e.g. with the use of a multiple unit dosing device) with a weight uniformity which is within the acceptable range of weight uniformity for tablets or capsules.
- weight uniformity can be found in the USP/NF 23/18 section 905, which is hereby incorporated by reference in its entirety for all purposes.
- the invention also provides methods of preparing fast melt multiparticulate dosage forms and systems disclosed herein.
- the invention further provides methods of preparing fast melt multiparticulate dosage forms without the use of an aqueous fluid as a processing aid.
- the invention additionally provides methods of preparing multiple unit delivery systems containing fast melt multiparticulate dosage forms in accordance with the invention.
- the invention also provides methods of preparing fast melt multiparticulate dosage forms having a desired particle size range.
- the invention further provides methods of administering an active agent comprising administering a fast melt multiparticulate dosage form.
- the invention additionally provides methods of administering an active agent comprising administering a fast melt multiparticulate dosage form via the use of a multiple unit delivery system.
- the present invention is directed to a drug formulation for gastrointestinal deposition comprising a non-compressed free flowing plurality of particles comprising an active agent and a water-soluble excipient, the particles having a mean diameter of greater than 10 ⁇ m to about 1 mm, the particles comprising at least about 50% drug and the formulation dissolving in a patient's mouth within 1 minute after administration without the co-administration of a fluid.
- the invention is directed to a method of treating a patient with an active agent for gastrointestinal deposition comprising administering a formulation comprising a non-compressed free flowing plurality of particles comprising an active agent and a water-soluble excipient, the particles having a mean diameter of greater than 10 ⁇ m to about 1 mm, and the formulation dissolving in a patient's mouth within 1 minute after administration without the co-administration of a fluid.
- the invention is directed to a drug delivery system for delivery of a drug for gastrointestinal deposition.
- the system comprises a multiple unit dosing device comprising a housing and an actuator, the device containing multiple doses of a fast melt multiparticulate formulation, the device upon actuation delivering a unit dose of the fast melt multiparticulates for gastrointestinal deposition, the multiparticulates having a mean particle size of greater than 10 ⁇ m and preferably less than about 1 mm in order to minimize pulmonary deposition of the multiparticulates and such that an effective dose of the drug cannot be delivered into the lower lung of a human patient.
- the drug delivery system can be used to administer the unit dose of fast melt multiparticulates into the oral cavity of the patient (in-vivo) or to dispense the unit dose into an intermediate receptacle (ex-vivo) for subsequent gastrointestinal deposition.
- Oral drug delivery systems and devices for oral powders are disclosed in WO01/64182, hereby incorporated by reference in its entirety for all purposes.
- the invention provides a method of preparing a drug delivery system for delivering multiple doses of a drug for gastrointestinal deposition comprising preparing a fast melt multiparticulate drug formulation in a manner wherein the drug particles when placed in the oral cavity are not deposited in any substantial amount to the lungs; and placing multiple unit doses of the fast melt drug formulation in a device which meters a single unit dose for delivery.
- the invention provides a method of treating a patient in need of multiple doses of a drug for gastrointestinal deposition comprising preparing fast melt multiparticulates in a manner wherein the drug particles when placed in the oral cavity are not deposited in any substantial amount to the lungs and dissolve or disperse in the mouth within 1 minute after administration, placing multiple unit doses of the fast melt multiparticulates in a device which meters a single unit dose for delivery and either (a) administering the unit dose into the oral cavity of a patient or(b) dispensing the unit dose into an intermediate receptacle and thereafter administering the unit dose into the oral cavity of the patient.
- the particles of the invention comprise at least about 50% drug; at least about 60% drug; at least about 70% drug; at least about 80% drug; or at least about 90% drug.
- low doses of up to 20%, 10% or 5% of drug or active agent are carried by the inventive particles.
- the invention provides a method for delivery of a drug comprising delivering fast melt multiparticulates comprising drug particles via the use of a multiple unit dosing device comprising a housing and an actuator, the device upon actuation delivering a unit dose of the fast melt multiparticulates, and thereafter re-using the device to deliver additional unit doses of the fast melt multiparticulates at appropriate dosing intervals.
- the unit dose comprises a discreet collection of fast melt multiparticulates.
- a “discreet collection” means that the fast melt multiparticulates are in the form of a non-compressed free flowing unit and not dispersed in a cloud or mist, which effectively minimizes inhalation of the active agent into the lungs of the patient.
- the unit dose can be include from about 0.01 mg to about 1.5 g of active agent.
- the dose of active agent can be from about 1 mg to about 100 mg, or from about 10 mg to about 50 mg.
- the mean diameter of the fast melt multiparticulates is of a size which minimizes their capacity to be inhaled into the lower lung.
- the mean particle size of the drug particles (or agglomerates) is greater than 10 ⁇ m, preferably greater than about 50 ⁇ m or greater than about 75 ⁇ m.
- the mean particle size range of the drug particles is from about 100 ⁇ m to about 1 mm, preferably from about 50 ⁇ m to about 500 ⁇ m.
- greater than 80% of the particles have the above disclosed diameter (not mean diameter), e.g. 80% of the drug particles have a diameter of greater than 10 ⁇ m, or a diameter of from about 100 ⁇ m to about 1 mm.
- greater than about 90% of the particles have the above disclosed diameter.
- the mean diameter of the fast melt multiparticulates does not vary by greater than about 20%, preferably not greater than about 15% and most preferably not greater than about 10%.
- the multiple doses of the fast melt formulation are contained in a reservoir.
- the reservoir can contain an amount of multiparticulates to provide any number of unit doses, e.g. from about 2 doses to about 400 doses.
- the reservoir has a sufficient quantity of to provide e.g. a days supply, a months supply or a years supply of doses, e.g. 30 or 365 for once daily dosing for a month or year, respectively.
- certain embodiments of the invention include a counter or indicator to display the number of doses remaining in the system or the number of doses actuated.
- the unit doses are individually metered prior to actuation, e.g., in the form of capsules or blisters or preferably in the form of sachets, wherein each sachet contains one individual unit dose.
- the system can be capable of containing any multiple of pre-metered unit doses, e.g. from about 2 to about 400 sachets.
- the term “device” refers to an apparatus capable of delivering a unit dose of drug.
- system refers to a drug delivery device in combination with a fast melt multiparticulate formulation having the specifications disclosed herein, e.g. drug particle size, excipient type, etc.
- disc collection refers to a non-compressed free flowing unit of multiparticulates with minimal particulate matter being dispersed in the surrounding environment (e.g., as a cloud or mist).
- drug refers to any agent which is capable of providing a therapeutic effect to a patient upon gastrointestinal deposition. This encompasses all drugs which are intended for absorption for a systemic effect (regardless of their actual bioavailability) as well as drugs intended for a local effect in the gut and/or oral cavity, e.g. nystatin, antibiotics or local anaesthetics.
- particle size refers to the diameter of the particle.
- gastrointestinal deposition means the intended deposit of the unit dose in the gastrointestinal system for e.g., absorption for a systemic effect or to exert a local effect.
- Pulmonary deposition means the intended deposit of drug into the lungs in order to provide a pharmaceutical effect, regardless that the unit dose may enter the oral cavity prior to pulmonary deposition.
- dispense when used in connection with the devices and systems of the present invention, means that the device or system delivers the unit dose ex vivo with the intent of subsequent administration to a mammal.
- the device or system can dispense the unit dose into a food, a liquid, a spoon, or another intermediate receptacle.
- administer when used in connection with the devices and systems of the present invention, means that the device or system delivers the unit dose in vivo, i.e., directly into the gastrointestinal tract of a mammal.
- delivery is meant to cover all ex vivo and in vivo delivery, i.e., dispensing and administering, respectively.
- patient refers to humans as well as other mammals in need of a therapeutic agent, e.g., household pets or livestock. This term also refers to humans or mammals in need of or receiving prophylactic treatment.
- fast melt means a formulation which dissolving or disperses in a patient's mouth within 1 minute after administration without the co-administration of a fluid.
- the formulation dissolving or disperses in a patient's mouth within 30 seconds, or 15 seconds after administration without the co-administration of a fluid
- the term “disperses” means that the administered formulation becomes hydrated in the mouth and the particles of the formulation become suspended is saliva, such that the multiparticulate formulation is wetted and easily swallowed.
- the particulates are defined functionally with respect to the fact that they are of a size such that an effective dose cannot be delivered into the lower lung of a human patient.
- this definition should be understood to mean that a small percentage of drug (but not an amount effective to render a therapeutic effect) may in fact be inadvertently delivered to the lungs of the patient.
- this definition is meant to define the particles, but not to limit the use of the invention to the treatments of humans only.
- the invention may be used for delivering doses of drugs to other mammals as well.
- dry powder inhalation or insufflation formulations must consist of particles of a size of about 2 microns in diameter in order for the particles, when inhaled, to reach the peripheral or “deep” lung, including alveoli. Particles larger than 10 microns in diameter are not able to reach the deep lung when inhaled because they are collected on the back of the throat and upper airways in humans. Therefore, known powder delivery systems have been formulated with particle sizes of less than 10 microns in order for the particles to reach the intended site of action, the pulmonary system.
- powder delivery devices have not contemplated delivery of particles from a multi-dose delivery device to achieve gastrointestinal deposition, and therefore have avoided the use of drug particles having a large size, e.g. greater than 10 microns.
- WO01/64182 it has been a surprising discovery that drug particles greater than 10 microns can be delivered from a multi-use drug delivery device for gastrointestinal deposition in a patient in order to minimize the inhalation of the drug particles into the lungs, in order to have substantially all of the dose deposited in the gastrointestinal system.
- powders that can be used in such devices can exhibit fast melt properties in order to provide the benefits of such formulations.
- the powders can be used in the device or can be administered without the use of the device, e.g., by using a sachet.
- fast melt multiparticulates of the present invention are not intended to be compressed, a high load formulation of the active agent is ascertainable. This is due to the fact that excipients which must be included in prior art fast melt tablets (e.g., fillers in order to provide bulk for tableting and disintegrants to provide a breakdown of the tablet upon administration) need not be included in the present formulations, or included to a lesser extent. As the fast melt formulations can have lower excipient and a higher drug load, the resultant unit dose is smaller which decreases the necessary time for the dissolution or dispersion of the formulation upon oral delivery.
- excipients which must be included in prior art fast melt tablets e.g., fillers in order to provide bulk for tableting and disintegrants to provide a breakdown of the tablet upon administration
- the water-soluble excipient of the formulation can be a sugar alcohol including, but not limited to sorbitol, mannitol, maltitol, reduced starch saccharide, xylitol, reduced paratinose, erythritol, and combination thereof.
- suitable water-soluble excipients include gelatin, partially hydrolyzed gelatin, hydrolyzed dextran, dextrin, alginate and mixtures thereof.
- the formulations of the present invention preferably include a salivary stimulant including, but not limited to citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, succinic acid, acid anhydrides thereof, acid salts thereof and combinations thereof.
- a salivary stimulant including, but not limited to citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, succinic acid, acid anhydrides thereof, acid salts thereof and combinations thereof.
- the salivary stimulant can also be an effervescent agent, such as wherein the effervescence is the result of a reaction of a soluble acid source and an alkali metal carbonate or carbonate source.
- the carbonate sources can be selected from the group consisting of dry solid carbonate and bicarbonate salts such as sodium bicarbonate, sodium carbonate, potassium bicarbonate and potassium carbonate, magnesium carbonate and sodium sesquicarbonate, sodium glycine carbonate, L-lysine carbonate, arginine carbonate and amorphous calcium carbonate.
- the drug formulations of the present invention preferably comprise a sweetener such as a water-soluble artificial sweetener, including but not limited to soluble saccharin salts, such as sodium or calcium saccharin salts, cyclamate salts, acesulfam-K, the free acid form of saccharin and mixtures thereof.
- a sweetener such as a water-soluble artificial sweetener, including but not limited to soluble saccharin salts, such as sodium or calcium saccharin salts, cyclamate salts, acesulfam-K, the free acid form of saccharin and mixtures thereof.
- the sweetener can also comprise a dipeptide based sweetener such as L-aspartyl L-phenylalanine methyl ester.
- formulations of the present invention can also comprise further pharmaceutical excipients such as polyvinyl alcohol, polyvinylpyrrolidine, acacia or a combination thereof.
- the dissolution or dispersion of the formulation can be improved with the use of a surfactant, such as sodium lauryl sulphate (Texapon K 12), various polysorbates known under the trade name Tween, ethers of polyhydroxy ethylene fatty acids known under the trade name Brij, esters of polyhydroxy ethylene fatty acids known under the trade name Myrj, sodium desoxycholate, glycerol polyethylene glycol ricinoleate (Cremophor EL), polyoxyethylene-polyoxypropylene polymers known under the trade name Pluronic, and various polyalkoxy alkylene sterol ethers.
- a surfactant such as sodium lauryl sulphate (Texapon K 12)
- Tween various polysorbates known under the trade name Tween
- ethers of polyhydroxy ethylene fatty acids known under the trade name Brij
- esters of polyhydroxy ethylene fatty acids known under the trade name Myrj
- sodium desoxycholate glycerol polyethylene glyco
- the fast melt formulations of the present invention can also comprise starches, e.g., corn starch, or modified starches, e.g., sodium starch glycolate or mixtures thereof, in any proportions.
- Starches can provide increased salivation due to the porous nature of the starch. Increased salivation favours rapid dissolution or dispersion of the formulation upon oral administration.
- the formulation can further comprise a starch degrading enzyme will have a synergistic effect with the starch with respect to dissolution or dispersion.
- the enzymes upon being contacted with an aqueous solution will initiate conversion of the starch to mono and polysaccharides which quickly dissolve in the aqueous environment and further contribute to improving the taste of the multiparticulate formulation and increasing salivation.
- the enzymes can be chosen for their degradation effect on the starch and also for their stability over time, i.e. during the shelf-life of the fast melt multiparticulate formulation.
- the enzyme will be chosen from the group of starch degrading enzymes comprising alpha-amylase, beta-amylase, amyloglucosidase, debranching enzymes and glucose-fructose isomerase.
- the enzymes can be an equal mixture of amyloglucosidase and a-amylase.
- drug formulations in accordance with the invention are prepared by a process comprising melt granulating the water soluble excipient and the active agent to form a homogenous mixture.
- the process comprises melt coating the water-soluble excipient onto the active agent which can be optionally pregranulated with a pharmaceutically acceptable excipient.
- the water-soluble excipient is preferably a water-soluble alcohol such as xylitol.
- melt granulation and melt coating processes are particularly preferred processes of the present invention as it is not necessary to use an aqueous fluid as a processing aid.
- formulations in accordance with the invention can be prepared by subliming solvent from a composition comprising the active agent and the water soluble excipient and reducing the sublimed composition to the particles.
- the composition can further comprises an excipient selected from the group consisting of polyvinyl alcohol, polyvinylpyrrolidone, acacia or a combination thereof.
- the sublimation is preferably by freeze-drying and the solvent can be an aqueous solvent or a co-solvent comprising an aqueous solvent and an alcohol.
- a surfactant can also be included in such a formulation.
- fast melt formulations in accordance with the invention can be prepared by a process which comprises preparing a mixture comprising the active agent, the water soluble excipient and a solvent, freezing the mixture, vacuum drying the frozen mixture above a collapse temperature of the mixture to form a partially collapsed matrix network and reducing the sublimed composition to the particles.
- the mixture comprises the active agent, a gum, a carbohydrate base, and a solvent, wherein the gum is selected from the group consisting of acacia, guar, xanthan, tragacanth gum, and mixtures thereof, and the carbohydrate is selected from the group consisting of mannitol, dextrose, sucrose, lactose, maltose, maltodextrin, corn syrup solids, and mixtures thereof.
- the gum is selected from the group consisting of acacia, guar, xanthan, tragacanth gum, and mixtures thereof
- the carbohydrate is selected from the group consisting of mannitol, dextrose, sucrose, lactose, maltose, maltodextrin, corn syrup solids, and mixtures thereof.
- fast melt formulations in accordance with the invention can be prepared by a process which comprises preparing a mixture comprising the active agent, the water soluble excipient and an agar aqueous solution, solidifying the mixture into a jelly form, drying the jelly and reducing the dried composition into the particles.
- the drying can be effected by reduced pressure drying, aeration drying or freeze-drying.
- fast melt formulations in accordance with the invention can be prepared by a process which comprises melt spinning the active agent with the saccharide to form a mass of spun fibres and reducing the spun fibres to the particles.
- the saccharide can be sucrose or glucose.
- the invention is directed to a method of preparing a multiparticulate drug formulation for gastrointestinal deposition comprising preparing a non-compressed free flowing plurality of particles comprising a core comprising a drug and a pharmaceutically acceptable excipient as disclosed herein and air jet sieving the particles to separate the cores from fine particles; and thereafter overcoating the core with a functional coating as disclosed herein.
- the invention is also directed to compositions obtained using these methods.
- compositions of multiparticulates obtained using air jet sieving and methods thereof are not limited to the particular embodiments disclosed herein.
- the use of an air jet sieve is beneficial as the standard sieving techniques used with screens and meshes may not separate all of the desired fine particles as the fine particles may adhere to the surface of larger particles and thus not separate during the sieving process.
- the air jet sieving process utilizes a negative pressure to draw particles below a particular size range down through an appropriate screen or mesh.
- there is a combination of a downward negative pressure and an upward positive pressure which facilitates the de-agglomeration of the different particle sizes.
- the upward pressure can be introduced upwards from a rotating wand.
- An apparatus utilizing a negative downward pressure and an upward positive pressure through a rotating wand is a Micron Air Jet Sieve MAJS I/II manufactured by Hosakawa.
- the effect of humidity can have a negative impact of the flowability of particles (e.g., due to cohesiveness).
- This can be a particular problem with the present invention, which is directed to fast melt multiparticulates which are designed to absorb water.
- the unit doses of fast melt multiparticulates are premetered prior to actuation of the device. This reduces the contamination of the unit doses as compared to having the formulation in a multiple dose reservoir.
- the premetered unit doses are contained in sachets which minimize the effect of humidity and moisture on the formulation.
- Classes of drugs which are suitable in the present invention include antacids, anti-inflammatory substances, coronary dilators, cerebral dilators, peripheral vasodilators, anti-infectives, psychotropics, anti-manics, stimulants, anti-histamines, laxatives, decongestants, vitamins, gastrointestinal sedatives, anti-diarrheal preparations, anti-anginal drugs, vasodilators, anti-arrhythmics, anti-hypertensive drugs, vasoconstrictors and migraine treatments, anti-coagulants and anti-thrombotic drugs, analgesics, anti-pyretics, hypnotics, sedatives, anti-emetics, anti-nauseants, anti-convulsants, neuromuscular drugs, hyper- and hypoglycemic agents, thyroid and anti-thyroid preparations, diuretics, anti-spasmodics, uterine relaxants, mineral and nutritional additives, anti-obesity drugs, an
- Specific drugs include gastro-intestinal sedatives such as metoclopramide and propantheline bromide; antacids such as aluminum trisilicate, aluminum hydroxide, ranitidine and cimetidine; anti-inflammatory drugs such as phenylbutazone, indomethacin, naproxen, ibuprofen, flurbiprofen, diclofenac, dexamethasone, prednisone and prednisolone; coronary vasodilator drugs such as glyceryl trinitrate, isosorbide dinitrate and pentaerythritol tetranitrate; peripheral and cerebral vasodilators such as soloctidilum, vincamine, naftidrofuryl oxalate, co-dergocrine mesylate, cyclandelate, papaverine and nicotinic acid; anti-infective substances such as erythromycin stearate, ce
- antibiotics such as clarithromycin, amoxicillin erythromycin, ampicillin, penicillin, cephalosporins, e.g., cephalexin, pharmaceutically acceptable salts thereof and derivatives thereof.
- a particularly preferred agent is paracetamol (acetaminophen).
- Other preferred agents are NTHES such as ibuprofen, indomethacin, aspirin, diclofenac and pharmaceutically acceptable salts thereof.
- formulations in accordance with the invention do not include any non-steroidal anti-inflammatory drug (NSAID).
- NSAID non-steroidal anti-inflammatory drug
- the size of the unit dose is dependent on the amount of drug needed to provide the intended therapeutic effect and the amount of any pharmaceutically acceptable excipient which may be necessary. Typically, a unit dose of from about 0.01 mg to about 1.5 g would be sufficient to contain a therapeutically effective amount of the drug to be delivered, however, this range is not limiting and can be smaller or higher, depending on the amount of drug and excipient that is necessary.
- the formulation had a sweet taste and good mouthfeel.
- the dissolution of the paracetamol from the formulation was measured using a modified version of the standard USP test for measuring paracetamol (acetaminophen) dissolution.
- the test conditions involved stirring 333 mg of the formulation in 900 ml of water, buffered to pH 5.8 with a potassium phosphate buffer, at 37° C., using a paddle speed of 100 RPM (the standard USP paddle speed is 50 RPM). The results are set out below.
- the tastemasking properties of xylitol result from its negative heat of solution, which confers a cooling effect on dissolution on the oral cavity.
- This example details the use of erythritol, which has a greater negative heat of solution, to improve the degree of tastemasking.
- Formulations were prepared using erythritol as the melt binder from the following materials. Material % Composition Paracetamol 87 Erythritol 10 Aspartame 0.5 Acesulphame K 0.5 Maltodextrin M100 2
- Granular acetaminophen and erythritol were accurately weighed into a glass jar and blended at 42 rpm for 30 minutes using an inversion low shear mixer.
- the blend was transferred to a jacketed vessel maintained at a temperature of 121° C.
- the blend was mixed at an impeller speed sufficient to keep the whole powder bed moving (i.e. 222 RPM) using an overhead mixer for a time sufficient to allow homogenous distribution of the molten binder in the blend.
- the temperature was then reduced to 95° C. and the xylitol, aspartame fine, acesulphame potassium and maltodextrin added to the blend.
- the impeller speed was increased as required to provide continuous movement of the powder bed (i.e. 250 RPM).
- the formulation was cooled and then sieved using a 710 micron sieve to remove any large agglomerates, once distribution of the melt binder was complete.
- Example 5 exhibited improved tastemasking over example 2, with improved masking of the slight aftertaste which was evident in example 3 and minimal evidence of the aftertaste which was evident in example 4.
- the browning of the formulation which was observed in example 3 was not evident in this formulation due to the incorporation of maltodextrin in the second stage of melt coating.
- the dissolution of the paracetamol from the formulation was measured using the same test as that employed in Example 1, and the results are set out below.
- Example 5 The drug release profiles of the formulation of Example 5 versus that of the unformulated raw drug, i.e., granular acetaminophen, are shown in FIG. 1.
- Example 6 describes the use of materials capable of liberating carbon dioxide in aqueous conditions to facilitate tastemasking. The following materials were employed in this example. Material % Composition Paracetamol 77 Xylitol 20 Sodium Glycine Carbonate 1.2 Citric Acid Monohydrate 0.8 Acesulphame K 0.5 Aspartame 0.5
- Example 8 illustrates the use of polyethylene glycols (PEGs) as the water soluble melt binder.
- Granular paracetamol, erythritol, sodium glycine carbonate and citric acid monohydrate and 5% PEG6000 were accurately weighed into a glass jar and blended at 42 rpm for 30 minutes using an inversion low shear mixer. The blend was transferred to a jacketed vessel maintained at a temperature of 70° C. The blend was mixed at an impeller speed sufficient to keep the whole powder bed moving (i.e. 222 RPM) using an overhead mixer for a time sufficient to allow homogenous distribution of the molten binder in the blend.
- the remaining melt binder was added to the blend, along with the maltodextrin M100, aspartame and acesulphame potassium, and the impeller speed increased to provide continuous movement of the powder bed (i.e. 250 RPM).
- the formulation was cooled and then sieved using a 710 micron sieve to remove any large agglomerates, once distribution of the melt binder was complete.
- the resulting formulation exhibited pleasant taste, good mouthfeel and a slight bitter aftertaste; which is attributed to the presence of additional citric acid.
- the dissolution of the paracetamol from the formulation was measured using the same test as that employed in Example 1, and the results are set out below.
- Sumatriptan 50 mg (Final Formulation Mass 75.7 mg) A granulation of Sumatriptan was prepared containing 4% w/w PVP K-30 (aqueous) in a MP Micro fluid bed dryer. The drug and binder were granulated by the addition of water, using the down-spray method. The granulated material was dried, cooled and then screened through a 250 ⁇ m sieve and airjet sieved to remove particles below 1001 m. The resulting granules were then spray coated with an aqueous dispersion of Eudragit RD-100 plasticised with Triacetin. The quantity of coating was sufficient to achieve the required degree of tastemasking of the active (approximately 15% weight gain).
- the granules were then dried and cooled for hot melt coating with xylitol.
- the tastemasked Sumatriptan granules were loaded into a 1 litre-jacketed bowl for a modified Diosna P1-6 mixer-granulator (preheated at 95° C. for 10 minutes) with 1% Aspartame (or 0.5% Aspartame and 0.5% Acesulfame potassium) and 10% xylitol.
- An impeller speed of 50 RPM and a chopper speed of 50 RPM were selected to distribute the binder (xylitol) through the material.
- Mixing was continued at the elevated temperature for approximately 5 minutes before addition of a further 10% xylitol to the system. After another 5 minutes mixing, the bowl was cooled to 25° C. over 10 minutes. Once cooled the formulation was tested. It was found that improved tastemasking and drug release could be achieved by further addition of Triacetin to the Eudragit RD100 film coat.
- a melt-granulation of 75% Ranitidine, 20% PEG 6000 and 5% Aspartame was prepared using a one litre jacketed mixing bowl heated to a temperature sufficient to melt the PEG 6000 binder (i.e. 70° C.).
- the Ranitidine and Aspartame were equilibrated in the bowl for 10 minutes at an impeller speed of 300 RPM and a chopper speed of 150 RPM, after this time the PEG6000 was added and massing continued for another 3 minutes.
- the material was then emptied from the bowl, cooled on a metal tray at room temperature and then stored in sealed bags. It was found that incorporation of molar equivalents of citric acid monohydrate and sodium bicarbonate into the melt granulation improved the degree of tastemasking and aided the dispersion of the granules.
- a 5% w/w aqueous dispersion of maltodextrin containing 5% w/w domperidone was prepared and spray-coated onto microcrystalline cellulose spheres sufficient to achieve a 33% coating wt. gain using and MP-Micro Fluid Bed Dryer. The coated spheres were then dried and cooled for hot melt coating with xylitol. Using a modified Diosna P1-6 mixer-granulator the domperidone-loaded microcrystalline cellulose spheres were blended with 10% wt. gain of xylitol using a one litre jacketed mixing bowl heated to 95° C.
- Step 1 Spray Coating With Surelease
- Granular paracetamol was tastemasked by spray-coating with an aqueous dispersion of ethylcellulose in an MP-Micro Fluid Bed Dryer. Approximately a 15% wt. gain was required, depending on the degree of tastemasking. Once the desired weight of ethylcellulose had been added to the granules, the material was dried, cooled and then screened through a 250 ⁇ m sieve and airjet sieved to remove particles below 100 ⁇ m. Using a modified Diosna P1-6 mixer-granulator, the tastemasked paracetamol granules were then blended with 1% Aspartame and 10% xylitol in a one litre jacketed mixing bowl heated to 95° C.
- a granulation of equal quantities of aspartame and Acesulphame K was prepared using 4% w/w PVP K-30 (aqueous) in a MP Micro fluid bed dryer.
- the drug and binder were granulated by the addition of water, using the down-spray method.
- the granulated material was dried, cooled and then screened through a 250 ⁇ m sieve and airjet sieved to remove particles below 100 ⁇ m.
- the granules were dried and cooled for hot melt coating with xylitol.
- Using a modified Diosna P1-6 mixer-granulator the aspartame/acesulphame K granules were blended with 4% Loperamide and 10% wt.
- a granulation of 19.2% Benserazide Hydrochloride and 76.8% Levodopa was prepared using 4% w/w PVP K-30 (aqueous) in a MP Micro fluid bed dryer.
- the drug and binder were granulated by the addition of water, using the down-spray method.
- the granulated material was dried, cooled and then screened through a 250 ⁇ m sieve and airjet sieved to remove particles below 100 ⁇ m.
- the granules were dried and cooled for hot melt coating with Xylitol.
- the Co-Beneldopa granulation was blended with 10% xylitol in a one litre jacketed mixing bowl heated to 95° C. for 10 minutes.
- An impeller speed of 50 RPM and a chopper speed of 50 RPM were selected to distribute the binder through the material.
- Mixing was continued at the elevated temperature for approximately 5 minutes before addition of a further 10% xylitol to the system.
- Granular Aspirin having a particle size suitable for spray coating (i.e., between 100 and 5001 ⁇ m) was coated in an MP-Micro fluid bed dryer, using the down-spray coating module.
- An aqueous dispersion of 15% w/w Opadry® was prepared, which was sprayed onto the granular aspirin at a product temperature of between 40 and 45° C. to a weight gain of 10%.
- the coated material was dried before a 15% weight gain of an aqueous dispersion of 15% w/w Acryl-eze was added to the granules, at a product temperature of 25-35° C.
- the material was dried and cooled before being placed in a one litre jacketed bowl for the Diosna P1-6 mixer granulator.
- a blend of 60% enteric coated aspirin, 20% Mannitol, 10% Xyltiol 7% Peg 6000, 0.5% Aspartame, 0.5% Acesulfame Potassium and 2% Maltodextrin was equilibrated at 70° C. whilst mixing at an impellar speed of 50 RPM and a chopper speed of 50 RPM. Mixing was continued at the elevated temperature for approximately 5 minutes before the bowl was cooled to 25° C. for 10 minutes.
- the formulation met USP requirements for acid phase drug release, i.e., less than or equal to 10% dissolved in 2 hours in 0.1M HCl and greater than 80% released in 90 minutes in pH 6.8 phosphate buffer.
- Step 1 Drug Loading
- Chlorpheniramine maleate was dissolved in an aqueous dispersion of 10% Opadry®. A 15% weight gain of Opadry® was applied to 60-40 mesh non-pariel sugar spheres, in order to obtain an active drug content of approximately 8% w/w. The dispersion was applied to the sugar spheres at a product temperature of between 40 and 45° C. in an MP-Micro fluid bed dryer, using the down-spray coating module.
- Step 2 Sustained Release Coating
- Step 3 Melt Granulation
- a granulation of 8% Chlorpheniramine Maleate, 4% w/w PVP K-30 and 88% Xylitol was prepared in an MP Micro fluid bed dryer. The materials were granulated by the addition of water, using the down-spray method. The granulated material was dried, cooled and then screened through a 250 ⁇ m sieve and airjet sieved to remove particles below 1001 ⁇ m.
- a blend containing 50% Chlorpheniramine Granules, 25% Granular Mannitol, 10% Erythritol, 0.5% Aspartame, 0.5% Acesulfame Potassium, 1.2% Citric Acid Monohydrate, 0.8% Sodium Glycine Carbonate and 2% Maltodextrin was equilibrated at 70° C. in a one litre jacketed bowl for a Diosna P1-6 mixer-granulator for 10 minutes at an impellar speed of 50 RPM and a chopper speed of 50 RPM prior to the addition of 10% PEG6000. Mixing was continued at the elevated temperature for approximately 5 minutes before the bowl was cooled to 25° C. for 10 minutes.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Zoology (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Pain & Pain Management (AREA)
- Medicinal Preparation (AREA)
- Medical Preparation Storing Or Oral Administration Devices (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A drug formulation for gastrointestinal deposition, said formulation comprising a free flowing plurality of particles comprising an active agent and a water-soluble excipient, wherein the particles have a mean diameter of greater than about 10 ┘m to about 1 mm, and the formulation is capable of dissolving or dispersing in a patient's mouth within 1 minute after administration without the co-administration of a fluid.
Description
- This application claims priority from U.S. Provisional Application No. 60/362,307 filed on Mar. 7, 2002 and No. 60/366,710 filed Mar. 22, 2002, the entire disclosures of which are hereby incorporated by reference.
- The present is directed to fast melt multiparticulate formulations for oral use. The multiparticulates can be used in a multiple dose delivery device which dispenses a unit dose of the powder upon actuation, or can be packaged for dispensation in sachets or like unit dose containers.
- The most prominent mode of delivery of therapeutic agents is by the oral route by means of solid dosage forms such as tablets and capsules. Oral administration of solid dosage forms is more convenient and accepted than other modes of administration, e.g., parenteral administration. However, the manufacture, dispensing and administration of solid dosage forms are not without associated problems and drawbacks.
- With the manufacture of solid dosage forms, in addition to the active agent, it is necessary to combine other ingredients in the formulations for various reasons, such as to enhance physical appearance, to provide necessary bulk for tableting or capsuling, to improve stability, to improve compressibility or to aid in disintegration after administration. However, these added excipients have been shown to adversely influence the release, stability and bioavailability of the active ingredient. The added excipients are a particular problem with drugs which require a high dose in order to provide a therapeutic effect, e.g., biphosphonate drugs. The inclusion of the additional excipient can make the final tablet extremely large which could result in esophogeal damage due to the physical characteristics of the dosage form if it is not swallowed properly. Esophogeal damage can also be caused by toxicity caused by the drug itself, if the tablet becomes lodged in the throat or has an increased transit time through the esophagus, due to its increased size.
- Further, the tableting of certain drugs has many associated production problems. In particular, many drugs, e.g., paracetamol (acetaminophen), have poor compressibility and cannot be directly compressed into solid dosage forms. Consequently, such drugs must either be wet granulated or manufactured in a special grade in order to be tableted which increases manufacturing steps and production costs.
- The adherence to good manufacturing practices and process controls is essential in order to minimize dosage form to dosage form and batch to batch variations of the final product. Even strict adherence to these practices still is not a guarantee that acceptable variation will occur.
- With the high cost of industrial scale production and governmental approval of solid dosage forms, such formulations are often available in a limited number of strengths, which only meet the needs of the largest sectors of the population. Unfortunately, this practice leaves many patients without acceptable means of treatment and physicians in a quandary with respect to individualizing dosages to meet the clinical needs of their patients.
- The dispensing of oral solid dosage forms also makes the formulations susceptible to degradation and contamination due to repackaging, improper storage and manual handling.
- There are also many patients who are unable or unwilling to take conventional orally administered dosage forms. For some patients, the perception of unacceptable taste or mouth feel of a dose of medicine leads to a gag reflex action that makes swallowing difficult or impossible. Other patients, e.g., pediatric and geriatric patients, find it difficult to ingest typical solid oral dosage forms, e.g., due to tablet size.
- Other patients, particularly elderly patients, have conditions such as achlorhydria which hinders the successful use of oral solid dosage forms. Achlorhydria is a condition wherein there is an abnormal deficiency or absence of free hydrochloric acid in the gastric secretions of the stomach. This condition hinders the disintegration and/or dissolution of oral solid dosage forms, particularly dosage forms with high or insoluble excipient payloads. Thus, as the present dosage form is in fast melt multiparticulate form, it does not need to undergo disintegration and/or dissolution to the same extent as solid dosage forms
- Flavoured solutions/suspensions of some therapeutic agents have been developed to facilitate the oral administration of oral agents to patients normally having difficulty ingesting conventional solid oral dosage forms. While liquid formulations are more easily administered to the problem patient, liquid/suspension formulations are not without their own significant problems and restrictions. The liquid dose amount is not as easily controlled compared with tablet and capsule forms and many therapeutic agents are not sufficiently stable in solution/suspension form. Indeed, most suspension type formulations are typically reconstituted by the pharmacist and then have a limited shelf life even under refrigerated conditions. Another problem with liquid formulations which is not as much a factor with tablets and capsules is the taste of the active agent. The taste of some therapeutic agents is so unacceptable that liquid formulations are not a viable option. Further, solution/suspension type formulations are typically not acceptable where the active agent must be provided with a protective coating, e.g. a taste masking coating or an enteric coating to protect the active agent from the strongly acidic conditions of the stomach.
- Fast melt drug formulations have also been developed to facilitate the oral administration of oral agents to patients normally having difficulty ingesting conventional solid oral dosage forms. Fast melt formulations are typically in the form of tablets or lozenges that dissolve or disperse in a patient's mouth within a minute without the need of water or chewing. Drug delivery formulations which exhibit fast melt properties can improve patient compliance due to the ease of swallowing as well as the absence of a need for the co-administration of water or another fluid. Further, fast melt systems can be formulated as to have a superior taste and improved accuracy of dosing as compared to liquid preparations.
- Other formulations which have been contemplated in order to facilitate the oral administration of oral agents and to avoid the associated problems of solid dosage forms are multiparticulate dosage forms as disclosed in WO 01/64182, the contents of which are hereby incorporated by reference.
- According to a first aspect of the present invention, there is provided a drug formulation for gastrointestinal deposition, said formulation comprising a free flowing plurality of particles comprising an active agent and a water-soluble excipient, wherein the particles have a mean diameter of greater than about 10 μm to about 1 mm, and the formulation is capable of dissolving or dispersing in a patient's mouth within 1 minute after administration without the co-administration of a fluid.
- Thus, the present invention, in its first aspect, provides a formulation which exhibits the benefits of fast melt formulations as well as the benefits of multiparticulate formulations. It also facilitates the delivery of a wide range of therapeutic agents for gastrointestinal deposition and minimizes pulmonary deposition of materials having undesirable or unknown pulmonary toxicology but which are approved for oral delivery. In some embodiments, the formulation can contain minimal excipient and be used in a multiple dose delivery device which dispenses a unit dose of the formulation upon actuation. Such delivery devices are disclosed in WO 01/64182.
- In a second aspect, the present invention provides a drug formulation for gastrointestinal deposition, said formulation comprising a free flowing plurality of particles and including an active agent and a water-soluble excipient, wherein the particles have a mean diameter of greater than about 10 μm to about 1 mm, and the excipient has a negative heat of solution.
- A significant advantage of formulations in accordance with the second aspect of the invention is that, when administered via the oral cavity, the local cooling caused by the water-soluble excipient dissolving in saliva serves to mask the taste of the active agent in a manner which does not delay the release, or dissolution of the active agent itself.
- Preferably, formulations in accordance with the second aspect of the invention are capable of dissolving or dispersing in a patient's mouth within one minute after administration, without the co-administration of a fluid. Such preferred formulations, therefore, are also examples of the first aspect of the invention and will provide all of the aforementioned benefits associated with the first aspect of the invention.
- Drug formulations in accordance with either the first or the second aspect of the invention are preferably arranged for direct, un-encapsulated administration to a patient's oral cavity. It is also preferred for the particles to be non-compressed.
- In embodiments, the particles each include both active agent and water-soluble excipient. The particles can comprise a core and a coating, with the coating including a quantity of the water-soluble excipient.
- Preferably, and in accordance with either aspect of the invention, the particles are formed by melt-coating core particles with a coating material that includes (and may consist of) a quantity of the excipient, at a temperature below that at which the active agent melts or decomposes. Forming the particles in this manner is considered to provide them with surface properties that render them easily wetted and capable of rapidly absorbing water from their environment and, thus, able to facilitate the rapid dissolution or dispersion of the formulation, especially the active agent, when the formulation is exposed to an aqueous environment, such as in the oral cavity.
- A quantity of the active agent can be included in the core or core particles and/or in the coating or coating material. In some preferred embodiments, the coating or coating material is substantially free of active agent, whereas in others, the core is substantially free of active agent.
- In further embodiments of either aspect of the invention, the coating or coating material comprises a water-soluble or hydrophilic binder. Preferably, the binder melts or softens sufficiently to melt-coat the core particles at a temperature below that at which the active agent melts or decomposes. In further embodiments, the water-soluble excipient melts or softens sufficiently to melt-coat the core particles at a temperature below that at which the active agent melts or decomposes. In further preferred arrangements, the binder melts or softens sufficiently to melt-coat the core particles at a temperature below that at which the water-soluble excipient melts or decomposes. In some embodiments of the invention, the coating or coating material substantially completely covers the surface of the core or core particles.
- Thus, particles in accordance with the present invention can comprise a core that consists substantially or entirely of active agent surrounded by a coating that comprises water-soluble excipient either alone, or in combination with a water-soluble or hydrophilic binder. When the water-soluble excipient is employed alone in such particles, it is preferred for it to be capable of melting or softening sufficiently to melt-coat the core particles at a temperature below that at which the active agent melts or decomposes. Where a binder is employed, the water-soluble excipient need not be capable of melting or softening at a temperature below the melting or decomposition temperature of the active agent. However, when such a high melting point water-soluble excipient is employed, the binder should be capable both of melting or softening sufficiently to melt-coat the core particles at a temperature below that at which the active agent melts or decomposes, and of binding the water-soluble excipient in the coating.
- The core or core particles, in addition to including active agent, can also include a quantity of the water-soluble excipient and/or an additional excipient, which may also be water soluble, but which does not necessarily qualify as a water-soluble excipient in accordance with the present invention. For example, the core can comprise a granulation of such an additional excipient (e.g. polyvinyl alcohol, or polyvinylpyrrolidine) and active agent, or consist of a particle (e.g. a microcrystalline cellulose sphere) of additional excipient coated with active agent.
- In other embodiments in accordance with the invention, the core can consist entirely of water-soluble excipient. In such embodiments, the coat or coating material comprises active agent and either an additional quantity of water-soluble excipient, or a binder. When the coat or coating material comprises active agent and binder, additional water-soluble excipient can also be present in therein.
- It is preferred that formulations in accordance with either aspect of the present invention are formed by a process in which the active agent is not raised to or above its melting point, or a temperature at which a significant proportion thereof is caused to decompose.
- The melting point of the water-soluble excipient is preferably equal to or below 150, 120 or 110° C., and is preferably at least 40 or 50° C. Preferably, the excipient melts at around or below 100° C. The melting point of the binder, if employed, is preferably equal to or below 150, 120 or 110° C., and is preferably at least 40 or 50° C.
- More preferably, the binder melts at around or below 100° C. In certain embodiments, the melting point of the excipient exceeds that of the binder.
- The water-soluble excipient, preferably, has a heat of solution equal to or below −7 KCal/Kg. More preferably, the heat of solution of the water-soluble excipient is equal to or below −10, −15, −20, −25, or −30 KCal/Kg. The solubility in water of the water-soluble excipient is preferably at least 20, 30 or 40% w/w at 25° C.
- The water-soluble excipient is preferably a sugar, sugar alcohol, polyethylene glycol (PEG), or polyethylene oxide, and is preferably not lactose. Formulations in accordance with the invention, preferably, are lactose free. The preferred water-soluble excipients are the sugar alcohols including, but not limited to sorbitol, mannitol, maltitol, reduced starch saccharide, xylitol, reduced paratinose, erythritol, and combinations thereof. The preferred sugar is glucose. Other suitable water-soluble excipients include gelatin, partially hydrolyzed gelatin, hydrolyzed dextran, dextrin, alginate and mixtures thereof.
- Preferred binders include polyethylene glycols (PEG) and polyethylene oxides.
- In further preferred embodiments, the core or core particles include an additional excipient for controlling or delaying the release of the active agent. In this regard, the core or core particles can include a layer or coating of such an additional excipient encapsulating an inner core comprising the active agent. The additional excipient can be selected from those known to persons skilled in the art to be capable of controlling the release of an encapsulated active agent. Such excipients include those commonly used to provide enteric and sustained release coatings. Examples of the former include cellulose acetate phthalate, hydroxypropyl-methylcelluose phthalate, polymethacrylates, such as Eudragit® L 100-55 or L 30 D-55, and Shellac. Examples of the latter include ethylcellulose, hydroxypropyl-celluose, hydroxypropylmethylcelluose, and polymethacrylates, such as Eudragit® RL and RS film-coating systems.
- In alternative embodiments, formulations in accordance with the invention can provide rapid release of the active agent. In this regard, the term “rapid release” should be understood to mean that such formulations release at least 80% of their active agent within 45 minutes in standard dissolution tests. In the case of poorly soluble active agents, such formulations typically release at least 80% of their active agent within 40, 30, 20, 15 and preferably 10 minutes after being administered to a patient's oral cavity. In the case of more soluble active agents, such formulations typically release at least 80% of their active agent within 10, 7 and preferably 5 minutes after being administered to a patient's oral cavity. In particularly preferred embodiments of the invention, the active agent will dissolve into an aqueous environment more rapidly from a formulation in accordance with the invention than it would if it had not been incorporated in such a formulation.
- In a third aspect, the present invention provides a method of preparing a drug formulation in accordance with the first or second aspect of the invention, comprising forming the particles by melt-coating core particles with a coating material that includes a quantity of the water-soluble excipient, at a temperature below the melting point or decomposition temperature of the active agent.
- In a further aspect, the invention provides the use of a drug formulation in accordance with the first or second aspect of the invention, or a drug formulation prepared by a method in accordance with the third aspect of the invention, for the preparation of a medicament for treating a human or animal patient, wherein the formulation is administered directly and in an un-encapsulated form to the patient's oral cavity. The invention also provides a method of treating a human or animal patient, wherein a formulation in accordance with the first or second aspect of the invention, or prepared by a method in accordance with a third aspect of the invention, is administered in a un-encapsulated form directly into the patient's oral cavity.
- It is also possible for formulations in accordance with either the first aspect or the second aspect of the invention to include additional particles with different properties to those described above. For example, the additional particles may not include any active agent.
- Certain embodiments of the invention comprise a fast melt multiparticulate formulation which contains a salivary stimulant to facilitate hydration of the formulation and the swallowing of a unit dose of the multiparticulates upon oral delivery.
- Certain embodiments of the invention comprise a fast melt multiparticulate formulation which has a desired particle range in order to minimize pulmonary aspiration of particles.
- Fast melt multiparticulate formulations in accordance with the invention are, preferably, divisable into unit doses (e.g. with the use of a multiple unit dosing device) with a weight uniformity which is within the acceptable range of weight uniformity for tablets or capsules. A detailed discussion of weight uniformity can be found in the USP/NF 23/18 section 905, which is hereby incorporated by reference in its entirety for all purposes.
- The invention also provides methods of preparing fast melt multiparticulate dosage forms and systems disclosed herein. The invention further provides methods of preparing fast melt multiparticulate dosage forms without the use of an aqueous fluid as a processing aid.
- The invention additionally provides methods of preparing multiple unit delivery systems containing fast melt multiparticulate dosage forms in accordance with the invention.
- The invention also provides methods of preparing fast melt multiparticulate dosage forms having a desired particle size range.
- The invention further provides methods of administering an active agent comprising administering a fast melt multiparticulate dosage form.
- The invention additionally provides methods of administering an active agent comprising administering a fast melt multiparticulate dosage form via the use of a multiple unit delivery system.
- In certain embodiments, the present invention is directed to a drug formulation for gastrointestinal deposition comprising a non-compressed free flowing plurality of particles comprising an active agent and a water-soluble excipient, the particles having a mean diameter of greater than 10 μm to about 1 mm, the particles comprising at least about 50% drug and the formulation dissolving in a patient's mouth within 1 minute after administration without the co-administration of a fluid.
- In certain embodiments, the invention is directed to a method of treating a patient with an active agent for gastrointestinal deposition comprising administering a formulation comprising a non-compressed free flowing plurality of particles comprising an active agent and a water-soluble excipient, the particles having a mean diameter of greater than 10 μm to about 1 mm, and the formulation dissolving in a patient's mouth within 1 minute after administration without the co-administration of a fluid.
- In certain embodiments, the invention is directed to a drug delivery system for delivery of a drug for gastrointestinal deposition. The system comprises a multiple unit dosing device comprising a housing and an actuator, the device containing multiple doses of a fast melt multiparticulate formulation, the device upon actuation delivering a unit dose of the fast melt multiparticulates for gastrointestinal deposition, the multiparticulates having a mean particle size of greater than 10 μm and preferably less than about 1 mm in order to minimize pulmonary deposition of the multiparticulates and such that an effective dose of the drug cannot be delivered into the lower lung of a human patient. The drug delivery system can be used to administer the unit dose of fast melt multiparticulates into the oral cavity of the patient (in-vivo) or to dispense the unit dose into an intermediate receptacle (ex-vivo) for subsequent gastrointestinal deposition. Oral drug delivery systems and devices for oral powders are disclosed in WO01/64182, hereby incorporated by reference in its entirety for all purposes.
- In certain embodiments, the invention provides a method of preparing a drug delivery system for delivering multiple doses of a drug for gastrointestinal deposition comprising preparing a fast melt multiparticulate drug formulation in a manner wherein the drug particles when placed in the oral cavity are not deposited in any substantial amount to the lungs; and placing multiple unit doses of the fast melt drug formulation in a device which meters a single unit dose for delivery.
- In certain embodiments, the invention provides a method of treating a patient in need of multiple doses of a drug for gastrointestinal deposition comprising preparing fast melt multiparticulates in a manner wherein the drug particles when placed in the oral cavity are not deposited in any substantial amount to the lungs and dissolve or disperse in the mouth within 1 minute after administration, placing multiple unit doses of the fast melt multiparticulates in a device which meters a single unit dose for delivery and either (a) administering the unit dose into the oral cavity of a patient or(b) dispensing the unit dose into an intermediate receptacle and thereafter administering the unit dose into the oral cavity of the patient.
- In certain embodiments, the particles of the invention comprise at least about 50% drug; at least about 60% drug; at least about 70% drug; at least about 80% drug; or at least about 90% drug. In others, low doses of up to 20%, 10% or 5% of drug or active agent are carried by the inventive particles. In certain embodiments, the invention provides a method for delivery of a drug comprising delivering fast melt multiparticulates comprising drug particles via the use of a multiple unit dosing device comprising a housing and an actuator, the device upon actuation delivering a unit dose of the fast melt multiparticulates, and thereafter re-using the device to deliver additional unit doses of the fast melt multiparticulates at appropriate dosing intervals.
- In preferred embodiments of the invention, the unit dose comprises a discreet collection of fast melt multiparticulates. For purposes of the invention, a “discreet collection” means that the fast melt multiparticulates are in the form of a non-compressed free flowing unit and not dispersed in a cloud or mist, which effectively minimizes inhalation of the active agent into the lungs of the patient. The unit dose can be include from about 0.01 mg to about 1.5 g of active agent. For example, the dose of active agent can be from about 1 mg to about 100 mg, or from about 10 mg to about 50 mg.
- In certain embodiments of the invention, the mean diameter of the fast melt multiparticulates is of a size which minimizes their capacity to be inhaled into the lower lung. Typically, the mean particle size of the drug particles (or agglomerates) is greater than 10 μm, preferably greater than about 50 μm or greater than about 75 μm. In certain embodiments of the invention, the mean particle size range of the drug particles is from about 100 μm to about 1 mm, preferably from about 50 μm to about 500 μm. In preferred embodiments, greater than 80% of the particles have the above disclosed diameter (not mean diameter), e.g. 80% of the drug particles have a diameter of greater than 10 μm, or a diameter of from about 100 μm to about 1 mm. In other embodiments, greater than about 90% of the particles have the above disclosed diameter.
- In certain embodiments of the invention, the mean diameter of the fast melt multiparticulates does not vary by greater than about 20%, preferably not greater than about 15% and most preferably not greater than about 10%.
- In certain embodiments of the invention, the multiple doses of the fast melt formulation are contained in a reservoir. The reservoir can contain an amount of multiparticulates to provide any number of unit doses, e.g. from about 2 doses to about 400 doses. For ease in patient compliance, the reservoir has a sufficient quantity of to provide e.g. a days supply, a months supply or a years supply of doses, e.g. 30 or 365 for once daily dosing for a month or year, respectively.
- In order to aid in patient compliance, certain embodiments of the invention include a counter or indicator to display the number of doses remaining in the system or the number of doses actuated.
- In certain embodiments of the invention, the unit doses are individually metered prior to actuation, e.g., in the form of capsules or blisters or preferably in the form of sachets, wherein each sachet contains one individual unit dose. The system can be capable of containing any multiple of pre-metered unit doses, e.g. from about 2 to about 400 sachets.
- For purposes of the present invention, the term “device” refers to an apparatus capable of delivering a unit dose of drug.
- The term “system” refers to a drug delivery device in combination with a fast melt multiparticulate formulation having the specifications disclosed herein, e.g. drug particle size, excipient type, etc.
- The term “discreet collection” refers to a non-compressed free flowing unit of multiparticulates with minimal particulate matter being dispersed in the surrounding environment (e.g., as a cloud or mist).
- The term “drug” refers to any agent which is capable of providing a therapeutic effect to a patient upon gastrointestinal deposition. This encompasses all drugs which are intended for absorption for a systemic effect (regardless of their actual bioavailability) as well as drugs intended for a local effect in the gut and/or oral cavity, e.g. nystatin, antibiotics or local anaesthetics.
- The term “particle size” refers to the diameter of the particle.
- The term “deposition” means the deposit of the unit dose at the intended point of absorption and/or action. For example, gastrointestinal deposition means the intended deposit of the unit dose in the gastrointestinal system for e.g., absorption for a systemic effect or to exert a local effect. Pulmonary deposition means the intended deposit of drug into the lungs in order to provide a pharmaceutical effect, regardless that the unit dose may enter the oral cavity prior to pulmonary deposition.
- The term “dispense”, when used in connection with the devices and systems of the present invention, means that the device or system delivers the unit dose ex vivo with the intent of subsequent administration to a mammal. For example, the device or system can dispense the unit dose into a food, a liquid, a spoon, or another intermediate receptacle.
- The term “administer”, when used in connection with the devices and systems of the present invention, means that the device or system delivers the unit dose in vivo, i.e., directly into the gastrointestinal tract of a mammal.
- The term “deliver” is meant to cover all ex vivo and in vivo delivery, i.e., dispensing and administering, respectively.
- The term “patient” refers to humans as well as other mammals in need of a therapeutic agent, e.g., household pets or livestock. This term also refers to humans or mammals in need of or receiving prophylactic treatment.
- The term “fast melt” means a formulation which dissolving or disperses in a patient's mouth within 1 minute after administration without the co-administration of a fluid. Preferably, the formulation dissolving or disperses in a patient's mouth within 30 seconds, or 15 seconds after administration without the co-administration of a fluid
- The term “disperses” means that the administered formulation becomes hydrated in the mouth and the particles of the formulation become suspended is saliva, such that the multiparticulate formulation is wetted and easily swallowed.
- In certain embodiments, the particulates are defined functionally with respect to the fact that they are of a size such that an effective dose cannot be delivered into the lower lung of a human patient. However, this definition should be understood to mean that a small percentage of drug (but not an amount effective to render a therapeutic effect) may in fact be inadvertently delivered to the lungs of the patient. Also, this definition is meant to define the particles, but not to limit the use of the invention to the treatments of humans only. The invention may be used for delivering doses of drugs to other mammals as well.
- In this specification, there are references to the temperature at which the active agent or the water-soluble excipient decomposes. This temperature should be understood to be the temperature at and above which the active agent or excipient would decompose to a significant extent, if held there for sufficient time for the active agent or excipient to be processes by melt granulation.
- In general, it has been recognized in the art that dry powder inhalation or insufflation formulations must consist of particles of a size of about 2 microns in diameter in order for the particles, when inhaled, to reach the peripheral or “deep” lung, including alveoli. Particles larger than 10 microns in diameter are not able to reach the deep lung when inhaled because they are collected on the back of the throat and upper airways in humans. Therefore, known powder delivery systems have been formulated with particle sizes of less than 10 microns in order for the particles to reach the intended site of action, the pulmonary system. Known powder delivery devices have not contemplated delivery of particles from a multi-dose delivery device to achieve gastrointestinal deposition, and therefore have avoided the use of drug particles having a large size, e.g. greater than 10 microns. By virtue of the invention disclosed in Applicants co-pending application, WO01/64182, it has been a surprising discovery that drug particles greater than 10 microns can be delivered from a multi-use drug delivery device for gastrointestinal deposition in a patient in order to minimize the inhalation of the drug particles into the lungs, in order to have substantially all of the dose deposited in the gastrointestinal system. By virtue of the present invention, powders that can be used in such devices can exhibit fast melt properties in order to provide the benefits of such formulations. The powders can be used in the device or can be administered without the use of the device, e.g., by using a sachet.
- As the fast melt multiparticulates of the present invention are not intended to be compressed, a high load formulation of the active agent is ascertainable. This is due to the fact that excipients which must be included in prior art fast melt tablets (e.g., fillers in order to provide bulk for tableting and disintegrants to provide a breakdown of the tablet upon administration) need not be included in the present formulations, or included to a lesser extent. As the fast melt formulations can have lower excipient and a higher drug load, the resultant unit dose is smaller which decreases the necessary time for the dissolution or dispersion of the formulation upon oral delivery.
- The water-soluble excipient of the formulation can be a sugar alcohol including, but not limited to sorbitol, mannitol, maltitol, reduced starch saccharide, xylitol, reduced paratinose, erythritol, and combination thereof. Other suitable water-soluble excipients include gelatin, partially hydrolyzed gelatin, hydrolyzed dextran, dextrin, alginate and mixtures thereof.
- The formulations of the present invention preferably include a salivary stimulant including, but not limited to citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, succinic acid, acid anhydrides thereof, acid salts thereof and combinations thereof.
- The salivary stimulant can also be an effervescent agent, such as wherein the effervescence is the result of a reaction of a soluble acid source and an alkali metal carbonate or carbonate source. The carbonate sources can be selected from the group consisting of dry solid carbonate and bicarbonate salts such as sodium bicarbonate, sodium carbonate, potassium bicarbonate and potassium carbonate, magnesium carbonate and sodium sesquicarbonate, sodium glycine carbonate, L-lysine carbonate, arginine carbonate and amorphous calcium carbonate.
- The drug formulations of the present invention preferably comprise a sweetener such as a water-soluble artificial sweetener, including but not limited to soluble saccharin salts, such as sodium or calcium saccharin salts, cyclamate salts, acesulfam-K, the free acid form of saccharin and mixtures thereof. The sweetener can also comprise a dipeptide based sweetener such as L-aspartyl L-phenylalanine methyl ester.
- The formulations of the present invention can also comprise further pharmaceutical excipients such as polyvinyl alcohol, polyvinylpyrrolidine, acacia or a combination thereof.
- The dissolution or dispersion of the formulation can be improved with the use of a surfactant, such as sodium lauryl sulphate (Texapon K 12), various polysorbates known under the trade name Tween, ethers of polyhydroxy ethylene fatty acids known under the trade name Brij, esters of polyhydroxy ethylene fatty acids known under the trade name Myrj, sodium desoxycholate, glycerol polyethylene glycol ricinoleate (Cremophor EL), polyoxyethylene-polyoxypropylene polymers known under the trade name Pluronic, and various polyalkoxy alkylene sterol ethers.
- The fast melt formulations of the present invention can also comprise starches, e.g., corn starch, or modified starches, e.g., sodium starch glycolate or mixtures thereof, in any proportions. Starches can provide increased salivation due to the porous nature of the starch. Increased salivation favours rapid dissolution or dispersion of the formulation upon oral administration.
- When a starch is present in the formulation, the formulation can further comprise a starch degrading enzyme will have a synergistic effect with the starch with respect to dissolution or dispersion. The enzymes upon being contacted with an aqueous solution will initiate conversion of the starch to mono and polysaccharides which quickly dissolve in the aqueous environment and further contribute to improving the taste of the multiparticulate formulation and increasing salivation.
- The enzymes can be chosen for their degradation effect on the starch and also for their stability over time, i.e. during the shelf-life of the fast melt multiparticulate formulation. Advantageously, the enzyme will be chosen from the group of starch degrading enzymes comprising alpha-amylase, beta-amylase, amyloglucosidase, debranching enzymes and glucose-fructose isomerase. In certain embodiments, the enzymes can be an equal mixture of amyloglucosidase and a-amylase.
- In certain embodiments, drug formulations in accordance with the invention are prepared by a process comprising melt granulating the water soluble excipient and the active agent to form a homogenous mixture. In an alternate embodiment, the process comprises melt coating the water-soluble excipient onto the active agent which can be optionally pregranulated with a pharmaceutically acceptable excipient.
- In such processes, the water-soluble excipient is preferably a water-soluble alcohol such as xylitol.
- The melt granulation and melt coating processes are particularly preferred processes of the present invention as it is not necessary to use an aqueous fluid as a processing aid. This results in a process which can be used for a wide variety of active agents, including those agents which would be susceptible to degradation upon contact with water. Accordingly, such processes provide advantages over many prior art processes for making fast melt systems which rely on water as a processing aid. These prior art processes would not be suitable for water liable drugs as such processes would result in degradation of the drug during the manufacturing process and during storage due to residual moisture in the final product.
- In certain embodiments, formulations in accordance with the invention can be prepared by subliming solvent from a composition comprising the active agent and the water soluble excipient and reducing the sublimed composition to the particles. In such embodiments, the composition can further comprises an excipient selected from the group consisting of polyvinyl alcohol, polyvinylpyrrolidone, acacia or a combination thereof. The sublimation is preferably by freeze-drying and the solvent can be an aqueous solvent or a co-solvent comprising an aqueous solvent and an alcohol. A surfactant can also be included in such a formulation.
- In certain embodiments, fast melt formulations in accordance with the invention can be prepared by a process which comprises preparing a mixture comprising the active agent, the water soluble excipient and a solvent, freezing the mixture, vacuum drying the frozen mixture above a collapse temperature of the mixture to form a partially collapsed matrix network and reducing the sublimed composition to the particles. Preferably, the mixture comprises the active agent, a gum, a carbohydrate base, and a solvent, wherein the gum is selected from the group consisting of acacia, guar, xanthan, tragacanth gum, and mixtures thereof, and the carbohydrate is selected from the group consisting of mannitol, dextrose, sucrose, lactose, maltose, maltodextrin, corn syrup solids, and mixtures thereof.
- In certain embodiments, fast melt formulations in accordance with the invention can be prepared by a process which comprises preparing a mixture comprising the active agent, the water soluble excipient and an agar aqueous solution, solidifying the mixture into a jelly form, drying the jelly and reducing the dried composition into the particles. The drying can be effected by reduced pressure drying, aeration drying or freeze-drying.
- In certain embodiments, fast melt formulations in accordance with the invention can be prepared by a process which comprises melt spinning the active agent with the saccharide to form a mass of spun fibres and reducing the spun fibres to the particles. The saccharide can be sucrose or glucose.
- In order to achieve the desired lower limit of the particles size of the fast melt multiparticulate formulation of the invention, air jet sieving can be used to remove fine particles. In particular embodiments, the invention is directed to a method of preparing a multiparticulate drug formulation for gastrointestinal deposition comprising preparing a non-compressed free flowing plurality of particles comprising a core comprising a drug and a pharmaceutically acceptable excipient as disclosed herein and air jet sieving the particles to separate the cores from fine particles; and thereafter overcoating the core with a functional coating as disclosed herein.
- The invention is also directed to compositions obtained using these methods.
- The compositions of multiparticulates obtained using air jet sieving and methods thereof are not limited to the particular embodiments disclosed herein. The use of an air jet sieve is beneficial as the standard sieving techniques used with screens and meshes may not separate all of the desired fine particles as the fine particles may adhere to the surface of larger particles and thus not separate during the sieving process. The air jet sieving process utilizes a negative pressure to draw particles below a particular size range down through an appropriate screen or mesh. In another embodiment, there is a combination of a downward negative pressure and an upward positive pressure which facilitates the de-agglomeration of the different particle sizes. In other embodiments, the upward pressure can be introduced upwards from a rotating wand. An apparatus utilizing a negative downward pressure and an upward positive pressure through a rotating wand is a Micron Air Jet Sieve MAJS I/II manufactured by Hosakawa.
- The effect of humidity can have a negative impact of the flowability of particles (e.g., due to cohesiveness). This can be a particular problem with the present invention, which is directed to fast melt multiparticulates which are designed to absorb water. Accordingly, in preferred embodiments, the unit doses of fast melt multiparticulates are premetered prior to actuation of the device. This reduces the contamination of the unit doses as compared to having the formulation in a multiple dose reservoir. Preferably, the premetered unit doses are contained in sachets which minimize the effect of humidity and moisture on the formulation.
- Other multiple unit oral dosing devices, adapted contain the formulation in a reservoir or as premetered unit doses, which are useful in the present invention are disclosed in WO01/64182 hereby incorporated by reference.
- Classes of drugs which are suitable in the present invention include antacids, anti-inflammatory substances, coronary dilators, cerebral dilators, peripheral vasodilators, anti-infectives, psychotropics, anti-manics, stimulants, anti-histamines, laxatives, decongestants, vitamins, gastrointestinal sedatives, anti-diarrheal preparations, anti-anginal drugs, vasodilators, anti-arrhythmics, anti-hypertensive drugs, vasoconstrictors and migraine treatments, anti-coagulants and anti-thrombotic drugs, analgesics, anti-pyretics, hypnotics, sedatives, anti-emetics, anti-nauseants, anti-convulsants, neuromuscular drugs, hyper- and hypoglycemic agents, thyroid and anti-thyroid preparations, diuretics, anti-spasmodics, uterine relaxants, mineral and nutritional additives, anti-obesity drugs, anabolic drugs, erythropoietic drugs, anti-asthmatics, bronchodilators, expectorants, cough suppressants, mucolytics, drugs affecting calcification and bone turnover and anti-uricemic drugs. Specific drugs include gastro-intestinal sedatives such as metoclopramide and propantheline bromide; antacids such as aluminum trisilicate, aluminum hydroxide, ranitidine and cimetidine; anti-inflammatory drugs such as phenylbutazone, indomethacin, naproxen, ibuprofen, flurbiprofen, diclofenac, dexamethasone, prednisone and prednisolone; coronary vasodilator drugs such as glyceryl trinitrate, isosorbide dinitrate and pentaerythritol tetranitrate; peripheral and cerebral vasodilators such as soloctidilum, vincamine, naftidrofuryl oxalate, co-dergocrine mesylate, cyclandelate, papaverine and nicotinic acid; anti-infective substances such as erythromycin stearate, cephalexin, nalidixic acid, tetracycline hydrochloride, ampicillin, flucloxacillin sodium, hexamine mandelate and hexamine hippurate; neuroleptic drugs such as flurazepam, diazepam, temazepam, amitryptyline, doxepin, lithium carbonate, lithium sulfate, chlorpromazine, thioridazine, trifluperazine, fluphenazine, piperothiazine, haloperidol, maprotiline hydrochloride, imipramine and desmethylimipramine; central nervous stimulants such as methylphenidate, ephedrine, epinephrine, isoproterenol, amphetamine sulfate and amphetamine hydrochloride; antihistamic drugs such as diphenhydramine, diphenylpyraline, chlorpheniramine and brompheniramine; anti-diarrheal drugs such as bisacodyl and magnesium hydroxide; the laxative drug, dioctyl sodium sulfosuccinate; nutritional supplements such as ascorbic acid, alpha tocopherol, thiamine and pyridoxine; anti-spasmodic drugs such as dicyclomine and diphenoxylate; drugs affecting the rhythm of the heart such as verapamil, nifedipine, diltiazem, procainamide, disopyramide, bretylium tosylate, quinidine sulfate and quinidine gluconate; drugs used in the treatment of hypertension such as propranolol hydrochloride, guanethidine monosulphate, methyldopa, oxprenolol hydrochloride, captopril and hydralazine; drugs used in the treatment of migraine such as ergotamine; drugs affecting coagulability of blood such as epsilon aminocaproic acid and protamine sulfate; analgesic drugs such as acetylsalicylic acid, acetaminophen, codeine phosphate, codeine sulfate, oxycodone, dihydrocodeine tartrate, oxycodeinone, morphine, heroin, nalbuphine, butorphanol tartrate, pentazocine hydrochloride, cyclazacine, pethidine, buprenorphine, scopolamine and mefenamic acid; anti-epileptic drugs such as phenytoin sodium and sodium valproate; neuromuscular drugs such as dantrolene sodium; substances used in the treatment of diabetes such as tolbutamide, disbenase glucagon and insulin; drugs used in the treatment of thyroid gland dysfunction such as triiodothyronine, thyroxine and propylthiouracil, diuretic drugs such as furosemide, chlorthalidone, hydrochlorthiazide, spironolactone and triamterene; the uterine relaxant drug ritodrine; appetite suppressants such as fenfluramine hydrochloride, phentermine and diethylproprion hydrochloride; anti-asthmatic and bronchodilator drugs such as aminophylline, theophylline, salbutamol, orciprenaline sulphate and terbutaline sulphate; expectorant drugs such as guaiphenesin; cough suppressants such as dextromethorphan and noscapine; mucolytic drugs such as carbocisteine; anti-septics such as cetylpyridinium chloride, tyrothricin and chlorhexidine; decongestant drugs such as phenylpropanolamine and pseudoephedrine; hypnotic drugs such as dichloralphenazone and nitrazepam; anti-nauseant drugs such as promethazine theoclate; haemopoietic drugs such as ferrous sulphate, folic acid and calcium gluconate; uricosuric drugs such as sulphinpyrazone, allopurinol and probenecid; and calcification affecting agents such as biphosphonates, e.g., etidronate, pamidronate, alendronate, residronate, teludronate, clodronate and alondronate.
- Particularly preferred agents include antibiotics such as clarithromycin, amoxicillin erythromycin, ampicillin, penicillin, cephalosporins, e.g., cephalexin, pharmaceutically acceptable salts thereof and derivatives thereof.
- A particularly preferred agent is paracetamol (acetaminophen). Other preferred agents are NTHES such as ibuprofen, indomethacin, aspirin, diclofenac and pharmaceutically acceptable salts thereof.
- In certain preferred embodiments, however, formulations in accordance with the invention do not include any non-steroidal anti-inflammatory drug (NSAID).
- The size of the unit dose is dependent on the amount of drug needed to provide the intended therapeutic effect and the amount of any pharmaceutically acceptable excipient which may be necessary. Typically, a unit dose of from about 0.01 mg to about 1.5 g would be sufficient to contain a therapeutically effective amount of the drug to be delivered, however, this range is not limiting and can be smaller or higher, depending on the amount of drug and excipient that is necessary.
- The following examples serve to illustrate the invention, but should not be understood to be limiting in any respect.
- The following materials were employed in this example.
Material % Composition Paracetamol 75 Xylitol 24 Aspartame 0.5 Acesulphame K 0.5 - Method
- Granular paracetamol, aspartame fine, acesulphame potassium and 12% xylitol were accurately weighed into a glass jar and blended at 42 rpm for 30 minutes using an inversion low shear mixer. The blend was transferred to a jacketed vessel maintained at a temperature of 95° C. The blend was mixed at an impeller speed sufficient to keep the whole powder bed moving (i.e. 222 RPM) using an overhead mixer for a time sufficient to allow homogenous distribution of the molten binder in the blend. The remaining melt binder was added to the blend and the impeller speed increased to provide continuous movement of the powder bed (i.e. 250 RPM). The formulation was cooled and then sieved using a 710 micron sieve to remove any large agglomerates, once distribution of the melt binder was complete.
- Results
- The formulation had a sweet taste and good mouthfeel. The dissolution of the paracetamol from the formulation was measured using a modified version of the standard USP test for measuring paracetamol (acetaminophen) dissolution. The test conditions involved stirring 333 mg of the formulation in 900 ml of water, buffered to pH 5.8 with a potassium phosphate buffer, at 37° C., using a paddle speed of 100 RPM (the standard USP paddle speed is 50 RPM). The results are set out below.
- The following materials were employed in this example.
Material % Composition Paracetamol 77 Xylitol 20 Aspartame 0.5 Acesulphame K 0.5 Maltodextrin M100 2 - Method
- Granular paracetamol, aspartame fine, maltodextrin M100, acesulphame potassium and 10% xylitol were accurately weighed into a glass jar and blended at 42 rpm for 30 minutes using an inversion low shear mixer. The blend was transferred to a jacketed vessel maintained at a temperature of 95° C. The blend was mixed at an impeller speed sufficient to keep the whole powder bed moving (i.e. 222 RPM) using an overhead mixer for a time sufficient to allow homogenous distribution of the molten binder in the blend. The remaining melt binder was added to the blend and the impellar speed increased to provide continuous movement of the powder bed (i.e. 250 RPM). The formulation was cooled and then sieved using a 710 micron sieve to remove any large agglomerates, once distribution of the melt binder was complete.
- Results
-
- The tastemasking properties of xylitol result from its negative heat of solution, which confers a cooling effect on dissolution on the oral cavity. This example details the use of erythritol, which has a greater negative heat of solution, to improve the degree of tastemasking. Formulations were prepared using erythritol as the melt binder from the following materials.
Material % Composition Paracetamol 87 Erythritol 10 Aspartame 0.5 Acesulphame K 0.5 Maltodextrin M100 2 - Method
- Granular paracetamol, aspartame fine, maltodextrin M100, acesulphame potassium and 5% erythritol were accurately weighed into a glass jar and blended at 42 rpm for 30 minutes using an inversion low shear mixer. The blend was transferred to a jacketed vessel maintained at a temperature of 121° C. The blend was mixed at an impellar speed sufficient to keep the whole powder bed moving (i.e. 222 RPM) using an overhead mixer for a time sufficient to allow homogenous distribution of the molten binder in the blend. The remaining melt binder was added to the blend and the impellar speed increased to provide continuous movement of the powder bed (i.e. 250 RPM). The formulation was cooled and then sieved using a 710 micron sieve to remove any large agglomerates, once distribution of the melt binder was complete.
- Results
- Upon melt granulation it was observed that the formulation developed a slight brown discoloration. This was attributed to the thermal degredation of Maltodextrin M100. This was confirmed by the preparation of Example 4 in which there was no evidence of browning.
- The following materials were employed in this example.
Material % Composition Paracetamol 89 Erythritol 10 Aspartame 0.5 Acesulphame K 0.5 - Method
- Granular acetaminophen, aspartame fine, acesulphame potassium and 5% erythritol were accurately weighed into a glass jar and blended at 42 rpm for 30 minutes using an inversion low shear mixer. The blend was transferred to a jacketed vessel maintained at a temperature of 121° C. The blend was mixed at an impeller speed sufficient to keep the whole powder bed moving (i.e. 222 RPM using an overhead mixer for a time sufficient to allow homogenous distribution of the molten binder in the blend. The remaining melt binder (erythritol) was added to the blend and the impeller speed increased to provide continuous movement of the powder bed (i.e. 250 RPM). The formulation was cooled and then sieved using a 710 micron sieve to remove any large agglomerates, once distribution of the melt binder was complete.
- Dissolution profiles were not obtained for examples 3 and 4.
- The following materials were employed in this example.
Material % Composition Paracetamol 82 Erythritol 5 Xylitol 10 Maltodextrin M100 2 Aspartame 0.5 Acesulphame K 0.5 - Method
- Granular acetaminophen and erythritol were accurately weighed into a glass jar and blended at 42 rpm for 30 minutes using an inversion low shear mixer. The blend was transferred to a jacketed vessel maintained at a temperature of 121° C. The blend was mixed at an impeller speed sufficient to keep the whole powder bed moving (i.e. 222 RPM) using an overhead mixer for a time sufficient to allow homogenous distribution of the molten binder in the blend. The temperature was then reduced to 95° C. and the xylitol, aspartame fine, acesulphame potassium and maltodextrin added to the blend. The impeller speed was increased as required to provide continuous movement of the powder bed (i.e. 250 RPM). The formulation was cooled and then sieved using a 710 micron sieve to remove any large agglomerates, once distribution of the melt binder was complete.
- Results
- Example 5 exhibited improved tastemasking over example 2, with improved masking of the slight aftertaste which was evident in example 3 and minimal evidence of the aftertaste which was evident in example 4. The browning of the formulation which was observed in example 3 was not evident in this formulation due to the incorporation of maltodextrin in the second stage of melt coating. The dissolution of the paracetamol from the formulation was measured using the same test as that employed in Example 1, and the results are set out below.
- The drug release profiles of the formulation of Example 5 versus that of the unformulated raw drug, i.e., granular acetaminophen, are shown in FIG. 1. The particle size distributions of the formulation of Example 5 (“Special Granulate APAP”) versus that of the unformulated raw drug (“Paracetamol Special Granular”) are shown in FIG. 2.
- Example 6 describes the use of materials capable of liberating carbon dioxide in aqueous conditions to facilitate tastemasking. The following materials were employed in this example.
Material % Composition Paracetamol 77 Xylitol 20 Sodium Glycine Carbonate 1.2 Citric Acid Monohydrate 0.8 Acesulphame K 0.5 Aspartame 0.5 - Method
- Granular paracetamol, aspartame fine, sodium glycine carbonate, citric acid monohydrate, acesulphame potassium and 10% xylitol were accurately weighed into a glass jar and blended at 42 rpm for 30 minutes using an inversion low shear mixer. The blend was transferred to a jacketed vessel maintained at a temperature of 95° C. The blend was mixed at an impellar speed sufficient to keep the whole powder bed moving (i.e. 222 RPM using an overhead mixer for a time sufficient to allow homogenous distribution of the molten binder in the blend. The remaining melt binder was added to the blend and the impellar speed increased to provide continuous movement of the powder bed (i.e. 250 RPM. The formulation was cooled and then sieved using a 710 micron sieve to remove any large agglomerates, once distribution of the melt binder was complete.
- Results
- The formulation exhibited acceptable tastemasking. However, the addition of Maltodextrin M100, as shown in example 7, improved its mouthfeel.
- The following materials were employed in this example.
Material % Composition Paracetamol 77 Xylitol 18 Maltodextrin M100 2.0 Sodium Glycine Carbonate 1.2 Citric Acid Monohydrate 0.8 Acesulphame K 0.5 Aspartame 0.5 - Method
- Granular paracetamol, aspartame fine, sodium glycine carbonate, citric acid monohydrate, maltodextrin M100, acesulphame potassium and 9% xylitol were accurately weighed into a glass jar and blended at 42 rpm for 30 minutes using an inversion low shear mixer. The blend was transferred to a jacketed vessel maintained at a temperature of 95° C. The blend was mixed at an impeller speed sufficient to keep the whole powder bed moving (i.e. 222 RPM) using an overhead mixer for a time sufficient to allow homogenous distribution of the molten binder in the blend. The remaining melt binder was added to the blend and the impeller speed increased to provide continuous movement of the powder bed (i.e. 250 RPM). The formulation was cooled and then sieved using a 710 micron sieve to remove any large agglomerates, once distribution of the melt binder was complete.
- Results
- The addition of Maltodextrin M100 was shown to improve mouthfeel.
- Example 8 illustrates the use of polyethylene glycols (PEGs) as the water soluble melt binder.
- The following materials were employed in this example.
Material % Composition Paracetamol 80 Erythritol 5 PEG6000 Powder 10 Maltodextrin M100 2.0 Sodium Glycine Carbonate 1.2 Citric Acid Monohydrate 0.8 Acesulphame K 0.5 Aspartame 0.5 - Method
- Granular paracetamol, erythritol, sodium glycine carbonate and citric acid monohydrate and 5% PEG6000 were accurately weighed into a glass jar and blended at 42 rpm for 30 minutes using an inversion low shear mixer. The blend was transferred to a jacketed vessel maintained at a temperature of 70° C. The blend was mixed at an impeller speed sufficient to keep the whole powder bed moving (i.e. 222 RPM) using an overhead mixer for a time sufficient to allow homogenous distribution of the molten binder in the blend. The remaining melt binder was added to the blend, along with the maltodextrin M100, aspartame and acesulphame potassium, and the impeller speed increased to provide continuous movement of the powder bed (i.e. 250 RPM). The formulation was cooled and then sieved using a 710 micron sieve to remove any large agglomerates, once distribution of the melt binder was complete.
- Results
- The resulting formulation exhibited reasonable tastemasking and a slight aftertaste, but with excellent mouthfeel and rapid dispersibility.
- An additional approach to drug tastemasking is described where the citric acid monohydrate content is increased to locally modify the pH within the oral cavity and therefore limit drug dissolution.
- The following materials were employed in this example.
Material % Composition Paracetamol 77.2 Erythritol 10.0 PEG6000 Powder 7.0 Sodium starch Glycolate 2.0 Sodium Glycine Carbonate 1.2 Citric Acid Monohydrate 1.5 Acesulphame K 0.5 Aspartame 0.5 Powdered Lemon Flavour 0.1 - Method
- Using a Diosna P1-6 mixer-granulator equipped with a 1 litre jacketed bowl was heated at 55° C. for 10 minutes before the addition of the granular acetaminophen, erythritol, sodium starch glycolate, sodium glycine carbonate, citric acid monohydrate, aspartame fine, acesulphame potassium and powdered lemon flavour. This material was blended for a further 10 minutes prior to the addition of the PEG6000. An impeller speed of 50 RPM and a chopper speed of 50 RPM were selected to distribute the binder through the material. Mixing was continued at the elevated temperature for approximately 5 minutes before the bowl was cooled to 25° C. for 10 minutes.
- Results
- The resulting formulation exhibited pleasant taste, good mouthfeel and a slight bitter aftertaste; which is attributed to the presence of additional citric acid. The dissolution of the paracetamol from the formulation was measured using the same test as that employed in Example 1, and the results are set out below.
- Sumatriptan 50 mg (Final Formulation Mass 75.7 mg) A granulation of Sumatriptan was prepared containing 4% w/w PVP K-30 (aqueous) in a MP Micro fluid bed dryer. The drug and binder were granulated by the addition of water, using the down-spray method. The granulated material was dried, cooled and then screened through a 250 μm sieve and airjet sieved to remove particles below 1001 m. The resulting granules were then spray coated with an aqueous dispersion of Eudragit RD-100 plasticised with Triacetin. The quantity of coating was sufficient to achieve the required degree of tastemasking of the active (approximately 15% weight gain). The granules were then dried and cooled for hot melt coating with xylitol. The tastemasked Sumatriptan granules were loaded into a 1 litre-jacketed bowl for a modified Diosna P1-6 mixer-granulator (preheated at 95° C. for 10 minutes) with 1% Aspartame (or 0.5% Aspartame and 0.5% Acesulfame potassium) and 10% xylitol. An impeller speed of 50 RPM and a chopper speed of 50 RPM were selected to distribute the binder (xylitol) through the material. Mixing was continued at the elevated temperature for approximately 5 minutes before addition of a further 10% xylitol to the system. After another 5 minutes mixing, the bowl was cooled to 25° C. over 10 minutes. Once cooled the formulation was tested. It was found that improved tastemasking and drug release could be achieved by further addition of Triacetin to the Eudragit RD100 film coat.
- Lansoprazole 15 mg (Final Formulation Mass 20 mg)
- Using a Diosna P1-6 mixer-granulator, a melt-granulation of 75% Lansoprazole, 20% PEG 6000 and 5% Aspartame was prepared using a one litre jacketed mixing bowl heated to a temperature sufficient to melt the PEG 6000 binder (i.e. 70° C.). The Lansoprazole and Aspartame were equilibrated in the bowl for 10 minutes at an impeller speed of 300 RPM and a chopper speed of 150 RPM, after this time the PEG6000 was added and massing continued for another 3 minutes. The material was then emptied from the bowl, cooled on a metal tray at room temperature and then stored in sealed bags. It was found that incorporation of 5% of a low-viscosity Sodium Starch Glycolate into the granules improved the mouthfeel of this formulation without altering drug release or the degree of tastemasking.
- Ranitidine 150 mg (Final Formulation Mass 200 mg)
- Using a Diosna P1-6 mixer-granulator, a melt-granulation of 75% Ranitidine, 20% PEG 6000 and 5% Aspartame was prepared using a one litre jacketed mixing bowl heated to a temperature sufficient to melt the PEG 6000 binder (i.e. 70° C.). The Ranitidine and Aspartame were equilibrated in the bowl for 10 minutes at an impeller speed of 300 RPM and a chopper speed of 150 RPM, after this time the PEG6000 was added and massing continued for another 3 minutes. The material was then emptied from the bowl, cooled on a metal tray at room temperature and then stored in sealed bags. It was found that incorporation of molar equivalents of citric acid monohydrate and sodium bicarbonate into the melt granulation improved the degree of tastemasking and aided the dispersion of the granules.
- Domperidone 10 mg (Final Formulation Mass 100 mg)
- A 5% w/w aqueous dispersion of maltodextrin containing 5% w/w domperidone was prepared and spray-coated onto microcrystalline cellulose spheres sufficient to achieve a 33% coating wt. gain using and MP-Micro Fluid Bed Dryer. The coated spheres were then dried and cooled for hot melt coating with xylitol. Using a modified Diosna P1-6 mixer-granulator the domperidone-loaded microcrystalline cellulose spheres were blended with 10% wt. gain of xylitol using a one litre jacketed mixing bowl heated to 95° C. An impeller speed of 50 RPM and a chopper speed of 50 RPM were selected to distribute the binder through the material. Mixing was continued at the elevated temperature for approximately 5 minutes before addition of a further 10% xylitol to the system. After another 5 minutes mixing, the bowl was cooled to 25° C. over 10 minutes. Once cooled, the formulation was tested. It was found that the incorporation of 0.25-0.5% of hydroxypropylmethylcellulose to the xylitol improved the stability of the formulation.
- Paracetamol (Acetaminophen) 500 mg (Final Formulation Mass 745 mg)
- Step 1: Spray Coating With Surelease
- Granular paracetamol was tastemasked by spray-coating with an aqueous dispersion of ethylcellulose in an MP-Micro Fluid Bed Dryer. Approximately a 15% wt. gain was required, depending on the degree of tastemasking. Once the desired weight of ethylcellulose had been added to the granules, the material was dried, cooled and then screened through a 250 μm sieve and airjet sieved to remove particles below 100 μm. Using a modified Diosna P1-6 mixer-granulator, the tastemasked paracetamol granules were then blended with 1% Aspartame and 10% xylitol in a one litre jacketed mixing bowl heated to 95° C. for 10 minutes. An impeller speed of 50 RPM and a chopper speed of 50 RPM were selected to distribute the binder through the material. Mixing was continued at the elevated temperature for approximately 5 minutes before addition of a further 10% xylitol to the system. After another 5 minutes mixing the bowl was cooled to 25° C. over 10 minutes. Once cooled the formulation was tested. It was found that improved tastemasking and drug release could be achieved by further addition of glycerol to the ethylcellulose film coat.
- Loperamide 2 mg (Final Formulation Mass 50 mg)
- A granulation of equal quantities of aspartame and Acesulphame K was prepared using 4% w/w PVP K-30 (aqueous) in a MP Micro fluid bed dryer. The drug and binder were granulated by the addition of water, using the down-spray method. The granulated material was dried, cooled and then screened through a 250 μm sieve and airjet sieved to remove particles below 100 μm. The granules were dried and cooled for hot melt coating with xylitol. Using a modified Diosna P1-6 mixer-granulator the aspartame/acesulphame K granules were blended with 4% Loperamide and 10% wt. gain of xylitol using a one litre jacketed mixing bowl heated to 95° C. An impeller speed of 50 RPM and a chopper speed of 50 RPM were selected to distribute the binder through the material. Mixing was continued at the elevated temperature for approximately 5 minutes before addition of a further 10% xylitol to the system. After another 5 minutes mixing the bowl was cooled to 25° C. over 10 minutes. Once cooled the formulation was tested. It was found that the incorporation of 0.25-0.5% of hydroxypropylmethylcellulose to the xylitol improved the stability of the formulation.
- Co-Beneldopa 12.5 mg/50 mg (Final Formulation Mass 164.8 mg)
- A granulation of 19.2% Benserazide Hydrochloride and 76.8% Levodopa was prepared using 4% w/w PVP K-30 (aqueous) in a MP Micro fluid bed dryer. The drug and binder were granulated by the addition of water, using the down-spray method. The granulated material was dried, cooled and then screened through a 250 μm sieve and airjet sieved to remove particles below 100 μm. The granules were dried and cooled for hot melt coating with Xylitol. Using a modified Diosna P1-6 mixer-granulator the Co-Beneldopa granulation was blended with 10% xylitol in a one litre jacketed mixing bowl heated to 95° C. for 10 minutes. An impeller speed of 50 RPM and a chopper speed of 50 RPM were selected to distribute the binder through the material. Mixing was continued at the elevated temperature for approximately 5 minutes before addition of a further 10% xylitol to the system.
- After another 5 minutes mixing the bowl was cooled to 25° C. over 10 minutes. Once cooled the formulation was tested. It was found that by adding a 5% wt. gain of glyceryl palmitostearate and 1% wt. gain of aspartame, the degree of tastemasking was improved without adversely impeding drug release.
- Enteric coated Aspirin formulation
- Method
- Granular Aspirin, having a particle size suitable for spray coating (i.e., between 100 and 5001 μm) was coated in an MP-Micro fluid bed dryer, using the down-spray coating module. An aqueous dispersion of 15% w/w Opadry® was prepared, which was sprayed onto the granular aspirin at a product temperature of between 40 and 45° C. to a weight gain of 10%. The coated material was dried before a 15% weight gain of an aqueous dispersion of 15% w/w Acryl-eze was added to the granules, at a product temperature of 25-35° C. The material was dried and cooled before being placed in a one litre jacketed bowl for the Diosna P1-6 mixer granulator. A blend of 60% enteric coated aspirin, 20% Mannitol, 10% Xyltiol 7% Peg 6000, 0.5% Aspartame, 0.5% Acesulfame Potassium and 2% Maltodextrin was equilibrated at 70° C. whilst mixing at an impellar speed of 50 RPM and a chopper speed of 50 RPM. Mixing was continued at the elevated temperature for approximately 5 minutes before the bowl was cooled to 25° C. for 10 minutes.
- Results
- The formulation met USP requirements for acid phase drug release, i.e., less than or equal to 10% dissolved in 2 hours in 0.1M HCl and greater than 80% released in 90 minutes in pH 6.8 phosphate buffer.
- Controlled Release Chlorpheniramine Maleate Drug-Loaded Spheres
- Step 1: Drug Loading
- Chlorpheniramine maleate was dissolved in an aqueous dispersion of 10% Opadry®. A 15% weight gain of Opadry® was applied to 60-40 mesh non-pariel sugar spheres, in order to obtain an active drug content of approximately 8% w/w. The dispersion was applied to the sugar spheres at a product temperature of between 40 and 45° C. in an MP-Micro fluid bed dryer, using the down-spray coating module.
- Step 2: Sustained Release Coating
- An additional 5% coat of 10% Opadry® aqueous dispersion was added to the drug loaded spheres before the application of an aqueous dispersion of 15% w/w Surelease was applied. A weight gain of between 15 and 30% was applied to produce a formulation with the required release profile.
- Step 3: Melt Granulation
- The dried, 65% drug-loaded spheres were blended in a one litre jacketed bowl for the Diosna P1-6 mixer granulator with 15% Mannitol, 10% Erythritol, 7% Peg 6000, 0.5% Aspartame, 0.5% Acesulfame Potassium and 2% Maltodextrin and equilibrated at 70° C. whilst mixing at an impellar speed of 50 RPM and a chopper speed of 50 RPM. Mixing was continued at the elevated temperature for approximately 5 minutes before the bowl was cooled to 25° C. for 10 minutes.
- Results
Time (Hours) % Drug Release 2 20-30 4 35-45 6 45-55 12 60-70 - Immediate release Chlorpheniramine Maleate
- A granulation of 8% Chlorpheniramine Maleate, 4% w/w PVP K-30 and 88% Xylitol was prepared in an MP Micro fluid bed dryer. The materials were granulated by the addition of water, using the down-spray method. The granulated material was dried, cooled and then screened through a 250 μm sieve and airjet sieved to remove particles below 1001 μm. A blend containing 50% Chlorpheniramine Granules, 25% Granular Mannitol, 10% Erythritol, 0.5% Aspartame, 0.5% Acesulfame Potassium, 1.2% Citric Acid Monohydrate, 0.8% Sodium Glycine Carbonate and 2% Maltodextrin was equilibrated at 70° C. in a one litre jacketed bowl for a Diosna P1-6 mixer-granulator for 10 minutes at an impellar speed of 50 RPM and a chopper speed of 50 RPM prior to the addition of 10% PEG6000. Mixing was continued at the elevated temperature for approximately 5 minutes before the bowl was cooled to 25° C. for 10 minutes.
- 10 Chronotherapeutic Chlorpheniramine Maleate Blend Method
- A blend of 16.7 g of immediate-release chlorpheniramine maleate granules (Example 20) was blended with 83.3 g controlled-release chlorpheniramine maleate drug-loaded spheres (Example 19) at 42 rpm for 30 minutes using an inversion low shear mixer.
Results (Formulation mass 600 mg: active 24 mg) Time (Hours) Mean Drug Release (mg) n = 6 0.5 4.2 4 9.6 6 12.1 12 15.6
Claims (84)
1. A drug formulation for gastrointestinal deposition, said formulation comprising a free flowing plurality of particles comprising an active agent and a water-soluble excipient, wherein the particles have a mean diameter of greater than about 10 μm to about 1 mm, and the formulation is capable of dissolving or dispersing in a patient's mouth within 1 minute after administration without the co-administration of a fluid.
2. A drug formulation for gastrointestinal deposition, said formulation comprising a free flowing plurality of particles and including an active agent and a water-soluble excipient, wherein the particles have a mean diameter of greater than about 10 μm to about 1 mm, and the excipient has a negative heat of solution.
3. A drug formulation as claimed in claim 2 , wherein said particles each include both active agent and water-soluble excipient.
4. A drug formulation as claimed in claim 3 , wherein the particles comprise a core and a coating that includes a quantity of the excipient.
5. A drug formulation as claimed in claim 1 , wherein the particles are formed by melt-coating core particles with a coating material that includes a quantity of the excipient, at a temperature below the melting point or decomposition temperature of the active agent.
6. A drug formulation as claimed in claim 4 , wherein a quantity of the active agent is included in the core or core particles.
7. A drug formulation as claimed in claim 6 , wherein the coating or coating material is substantially free of active agent.
8. A drug formulation as claimed in claim 4 , wherein a quantity of the active agent is included in the coating or coating material.
9. A drug formulation as claimed in claim 8 , wherein the core or core particles are substantially free of active agent.
10. A drug formulation as claimed in claims 4, wherein the coating or coating material further comprises a water soluble or hydrophilic binder.
11. A drug formulation as claimed in claim 10 , wherein the binder melts or softens sufficiently to melt-coat the core particles at a temperature below the melting point or decomposition temperature of the active agent.
12. A drug formulation as claimed in claim 1 , wherein the excipient melts or softens sufficiently to melt-coat the core particles at a temperature below the melting point or decomposition temperature of the active agent.
13. A drug formulation as claimed in claim 11 , wherein the binder melts or softens sufficiently to melt-coat the core particles at a temperature below the melting point or decomposition temperature of the excipient.
14. A drug formulation as claimed in claims 4, wherein the coating or coating material substantially completely covers the surface of the core or core particles.
15. A drug formulation as claimed in claim 1 , wherein the core or core particles include a quantity of the water-soluble excipient and/or an additional, optionally, water soluble excipient.
16. A drug formulation as claimed in claim 15 , wherein, the core or each core particle comprises a granulation of said an additional excipient and active agent, or a particle of additional excipient coated with active agent.
17. A drug formulation as claimed in claim 1 , formed by a process in which the active agent is not raised to or above its melting point, or a temperature at which a significant proportion thereof is caused to decompose.
18. A drug formulation as claimed in claim 1 , wherein the melting point of the water-soluble excipient is equal to or below 150, 120 or 110° C.
19. A drug formulation as claimed in claim 18 , wherein the melting point of the water-soluble excipient is at least 40 or 50° C.
20. A drug formulation as claimed in claim 1 , wherein the melting point of the binder is equal to or below 150, 120 or 110° C.
21. A drug formulation as claimed in claim 20 , wherein the melting point of the binder is at least 40 or 50° C.
22. A drug formulation as claimed in claim 1 , wherein the melting point of the excipient exceeds that of the binder.
23. A drug formulation as claimed in claim 1 , wherein the water-soluble excipient has a heat of solution equal to or below −7 KCal/Kg.
24. A drug formulation as claimed in claim 23 , wherein the heat of solution of the water-soluble excipient is equal to or below −10, —15, −20, −25, or −30 KCal/Kg.
25. A drug formulation as claimed in claim 1 , wherein the solubility in water of the water-soluble excipient is at least 20, 30 or 40% w/w at 25° C.
26. A drug formulation as claimed in claim 1 , wherein the water-soluble excipient is a sugar, sugar alcohol, polyethylene glycol (PEG), polyethylene oxide, gelatin, partially hydrolyzed gelatin, hydrolyzed dextran, dextrin, alginate or a mixture of any of the foregoing.
27. A drug formulation as claimed in claim 26 , wherein the water-soluble excipient is a sugar alcohol or combination of sugar alcohols.
28. A drug formulation as claimed in claim 27 , wherein the sugar alcohol or sugar alcohols is or are sorbitol, mannitol, maltitol, reduced starch saccharide, xylitol, reduced paratinose, erythritol, or any combination thereof.
29. A drug formulation as claimed in claim 1 , wherein the binder includes a polyethylene glycol (PEG) and/or a polyethylene oxide.
30. A drug formulation as claimed in claim 1 , wherein the core or core particles include an additional excipient for controlling or delaying the release of the active agent.
31. A drug formulation as claimed in claim 30 , wherein the core or core particles include a layer or coating of said additional excipient encapsulating an inner core comprising the active agent.
32. A drug formulation as claimed in claim 30 , wherein said additional excipient provides an enteric or sustained release coating.
33. A drug formulation as claimed in claim 32 , wherein said additional excipient is selected from the group consisting of cellulose acetate phthalate, hydroxypropyl-methylcelluose phthalate, polymethacrylates, Shellac, ethylcellulose, hydroxypropyl-celluose, and hydroxypropylmethylcelluose.
34. A drug formulation as claimed in claim 1 , wherein said formulation dissolves in a patient's mouth within 30 or 15 seconds after administration without the coadministration of a fluid.
35. A drug formulation as claimed in claim 1 , wherein the particles comprise at least about 50%, 60%, or 75% drug.
36. A drug formulation as claimed in claim 1 further comprising a salivary stimulant.
37. A drug formulation as claimed in claim 1 , wherein said formulation further comprises an excipient selected from the group consisting of polyvinyl alcohol, polyvinylpyrrolidine, acacia and combinations thereof.
38. A drug formulation as claimed in claim 1 further comprising a water-soluble artificial sweetener.
39. A drug formulation as claimed in claim 38 , wherein said water soluble artificial sweetener is selected from the group consisting of soluble saccharin salts, such as sodium or calcium saccharin salts, cyclamate salts, acesulfam-K, the free acid form of saccharin and mixtures thereof.
40. A drug formulation as claimed in claim 1 further comprising a dipeptide based sweetener.
41. A drug formulation as claimed in claim 40 , wherein said dipeptide based sweetener is L-aspartyl L-phenylalanine methyl ester.
42. A drug formulation as claimed in claim 36 , wherein said salivary stimulant is selected from the group consisting of citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, succinic acid, acid anhydrides thereof, acid salts thereof and combinations thereof.
43. A drug formulation as claimed in claim 36 , wherein said salivary stimulant is an effervescent agent.
44. A drug formulation as claimed in claim 43 , wherein said effervescent agent is the result of a reaction of a soluble acid source and an alkali metal carbonate or carbonate source.
45. A drug formulation as claimed in claim 2 , wherein the formulation is capable of dissolving or dispersing in a patient's mouth within 1 minute after administration without the co-administration of a fluid.
46. A drug formulation as claimed in claim 1 , arranged for direct un-encapsulated administration to the oral cavity.
47. A drug formulation as claimed in claim 1 , wherein the particles are non-compressed.
48. A method of preparing a drug formulation as claimed in claim 1 , comprising forming the particles by melt-coating core particles with a coating material that includes a quantity of the water-soluble excipient and, optionally, a quantity of the binder, at a temperature below the melting point or decomposition temperature of the active agent.
49. Use of a drug formulation as claimed in claim 1 , or a drug formulation is prepared by a method as claimed in claim 48 , for the preparation of a medicament for treating a human or animal patient, wherein the formulation is administered directly and in an un-encapsulated form to the patient's oral cavity.
50. A method of treating a human or animal patient, wherein a formulation as claimed in claim 1 , is administered in a un-encapsulated form directly into the patient's oral cavity.
51. A drug delivery system comprising a dosing device comprising a housing and an actuator, said device containing at least one unit dose of a drug formulation as claimed in claim 1 , said device upon actuation delivering a unit dose of said drug formulation such that an effective dose of said drug cannot be delivered into the lower lung of a human patient.
52. The drug delivery system of claim 51 wherein said at least one unit dose is contained in a reservoir.
53. The drug delivery system of claim 51 further comprising a metering component to meter a unit dose from said reservoir upon actuation of said system.
54. The drug delivery system of claim 51 comprising multiple unit doses, wherein said unit doses are individually metered prior to said actuation.
55. The drug delivery system of claim 51 further comprising sachets, each sachet containing said individually metered unit dose.
56. The drug delivery system of claim 55 wherein said sachets are aligned linearly in the form of a strip.
57. The drug delivery system of claim 56 wherein said strip is in the form of a roll.
58. The drug delivery system of claim 57 further comprising blisters on a substrate base, each blister containing said individually metered unit dose, said blisters covered by a seal.
59. The system of claim 58 wherein said blisters are aligned linearly in the form of a strip.
60. The system of claim 59 wherein said strip is in the form of a roll.
61. A method of treating a patient with an active agent for gastrointestinal deposition comprising administering a formulation comprising a non-compressed free flowing plurality of particles comprising an active agent and a water-soluble excipient, said particles having a mean diameter of greater than 10 μm to about 1 mm, and said formulation dissolving in a patient's mouth within 1 minute after administration without the co-administration of a fluid.
62. A method of treating a patient with an active agent for gastrointestinal deposition comprising formulating a drug formulation comprising a non-compressed free flowing plurality of particles comprising an active agent and a water-soluble excipient, said particles having a mean diameter of greater than 10 μm to about 1 mm, and said formulation dissolving in a patient's mouth within 1 minute after administration without the co-administration of a fluid, containing said drug formulation in a drug delivery, said device upon actuation delivering a unit dose of said drug formulation such that an effective dose of said drug cannot be delivered into the lower lung of a human patient; and administering a unit dose of said particles to the oral cavity.
63. A method of preparing a drug delivery system for gastrointestinal deposition of an active agent comprising formulating a drug formulation comprising a non-compressed free flowing plurality of particles comprising an active agent and a water-soluble excipient, said particles having a mean diameter of greater than 10 μm to about 1 mm, and said formulation dissolving in a patient's mouth within 1 minute after administration without the coadministration of a fluid, containing said drug formulation in a drug delivery, said device upon actuation delivering a unit dose of said drug formulation such that an effective dose of said drug cannot be delivered into the lower lung of a human patient.
64. The system of claim 51 wherein said active agent is an antibiotic.
65. The system of claim 64 wherein said antibiotic is a macrolide antibiotic.
66. The system of claim 65 wherein said macrolide antibiotic is selected from the group consisting of erythromycin, dirithromycin, josamycin, midecamycin, kitasamycin, tylosin, roxithromycin, rokitamycin, oleandomycin, miocamycin, flurithromycin, rosaramicin, azithromycin, clarithromycin, and pharmaceutically acceptable salts thereof.
67. The system of claim 65 wherein said macrolide antibiotic is selected from the group consisting of erythromycin, clarithromycin, and pharmaceutically acceptable salts thereof
68. A method of treating a patient with a macrolide antibiotic for gastrointestinal deposition comprising administering a drug formulation for gastrointestinal deposition comprising a non-compressed free flowing plurality of particles comprising a macrolide antibiotic and a water-soluble excipient, said particles having a mean diameter of greater than 10 μm to about 1 mm, said formulation dissolving in a patient's mouth within 1 minute after administration without the coadministration of a fluid.
69. The method of claim 68 wherein said formulation dissolves in a patient's mouth within 30, or 15 seconds after administration without the coadministration of a fluid.
70. The method of claim 68 wherein said particles comprise at least about 50%, 60% or 75% drug.
71. A macrolide antibiotic formulation for gastrointestinal deposition comprising a non-compressed free flowing plurality of particles comprising a macrolide antibiotic and a water-soluble excipient, said particles having a mean diameter of greater than 10 μm to about 1 mm, said formulation dissolving in a patient's mouth within 1 minute after administration without the coadministration of a fluid.
72. A formulation for gastrointestinal deposition comprising a non-compressed free flowing plurality of particles comprising an active agent and a water-soluble excipient, said particles having a mean diameter of greater than 10 μm to about 1 mm, said formulation dissolving in a patient's mouth within 1 minute after administration without the co-administration of a fluid, said particles comprising less than 5% hydrophobic material.
73. The formulation of claim 72 wherein said particles are prepared by a process comprising melt granulating said water soluble excipient and the active agent to form a homogenous mixture.
74. The formulation of claim 72 wherein said particles are prepared by a process comprising melt coating said water soluble excipient onto said active agent.
75. The formulation of claim 73 which is prepared without the use of an aqueous fluid.
76. A drug formulation as claimed in claim 1 , wherein the water-soluble excipient is xylitol
77. A drug formulation as claimed in claim 1 , wherein the active agent is paracetamol.
78. A drug formulation as claimed in claim 1 , being adapted to provide both immediate release and controlled release of the active agent.
79. A drug formulation as claimed in claim 78 , comprising a free flowing plurality of particles comprising an active agent and a water-soluble excipient, wherein at least a portion of the particles comprise active agent and at least one delayed release excipient.
80. A drug formulation as claimed in claim 78 , wherein a first portion of the particles comprises at least one delayed release excipient, to provide controlled release of active agent, and a second portion of the particles does not include any delayed release excipients, to provide immediate release of active agent.
81. A method of treating a human or animal patient, wherein a formulation as claimed in claim 2 , is administered in a un-encapsulated form directly into the patient's oral cavity.
82. A drug delivery system comprising a dosing device comprising a housing and an actuator, said device containing at least one unit dose of a drug formulation as claimed in claim 2 , said device upon actuation delivering a unit dose of said drug formulation such that an effective dose of said drug cannot be delivered into the lower lung of a human patient.
83. A method of treating a human or animal patient, wherein a formulation prepared by a method as claimed in claim 48 , is administered in a un-encapsulated form directly into the patient's oral cavity.
84. A drug delivery system comprising a dosing device comprising a housing and an actuator, said device containing at least one unit dose of a drug formulation that was prepared by a method as claimed in claim 48 , said device upon actuation delivering a unit dose of said drug formulation such that an effective dose of said drug cannot be delivered into the lower lung of a human patient.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10/383,351 US20030175355A1 (en) | 2002-03-07 | 2003-03-07 | Fast melt multiparticulate formulations for oral delivery |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US36230702P | 2002-03-07 | 2002-03-07 | |
US36671002P | 2002-03-22 | 2002-03-22 | |
US10/383,351 US20030175355A1 (en) | 2002-03-07 | 2003-03-07 | Fast melt multiparticulate formulations for oral delivery |
Publications (1)
Publication Number | Publication Date |
---|---|
US20030175355A1 true US20030175355A1 (en) | 2003-09-18 |
Family
ID=27791705
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/383,408 Expired - Fee Related US6941948B2 (en) | 2002-03-07 | 2003-03-07 | Medicament storage and delivery devices |
US10/383,351 Abandoned US20030175355A1 (en) | 2002-03-07 | 2003-03-07 | Fast melt multiparticulate formulations for oral delivery |
US11/115,826 Abandoned US20050205083A1 (en) | 2002-03-07 | 2005-04-27 | Medicament storage and delivery devices |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/383,408 Expired - Fee Related US6941948B2 (en) | 2002-03-07 | 2003-03-07 | Medicament storage and delivery devices |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US11/115,826 Abandoned US20050205083A1 (en) | 2002-03-07 | 2005-04-27 | Medicament storage and delivery devices |
Country Status (5)
Country | Link |
---|---|
US (3) | US6941948B2 (en) |
EP (1) | EP1490031A1 (en) |
JP (1) | JP2005527508A (en) |
AU (1) | AU2003209475A1 (en) |
WO (1) | WO2003074029A1 (en) |
Cited By (26)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20040228804A1 (en) * | 2003-05-16 | 2004-11-18 | Jones Alonzo H. | Nasal administration of xylitol to a non-human mammal |
WO2005063203A2 (en) * | 2003-12-31 | 2005-07-14 | Vectura Ltd | Multiparticulate formulations for oral delivery |
US6941948B2 (en) | 2002-03-07 | 2005-09-13 | Vectura Drug Delivery | Medicament storage and delivery devices |
WO2006131806A2 (en) * | 2005-06-07 | 2006-12-14 | Pfizer Products Inc. | Multiparticulates comprising low-solubility drugs and carriers that result in rapid drug release |
EP1868583A1 (en) * | 2005-04-12 | 2007-12-26 | Elan Pharma International Limited | Controlled release compositions comprising a cephalosporin for the treatment of a bacterial infection |
WO2008023184A3 (en) * | 2006-08-24 | 2008-04-24 | Arrow Int Ltd | Solid dosage form |
US20080127972A1 (en) * | 2004-11-23 | 2008-06-05 | Vectura Limited | Dry Powder Inhaler Formulations Comprising Surface-Modified Particles With Anti-Adherent Additives |
US20080220078A1 (en) * | 2004-11-30 | 2008-09-11 | Vectura Limited | Pharmaceutical Formulations |
US20080287456A1 (en) * | 2004-05-28 | 2008-11-20 | Imaginot Pty Ltd | Oral Therapeutic Compound Delivery System |
US20090012109A1 (en) * | 2006-12-28 | 2009-01-08 | Brian Austad | Cyclopamine analogs |
US20090311327A1 (en) * | 2005-11-28 | 2009-12-17 | Imaginot Pty Ltd | Oral Therapeutic Compound Delivery System |
US20100190739A1 (en) * | 2008-12-15 | 2010-07-29 | Fleming And Company, Pharmaceuticals | Rapidly Dissolving Vitamin Formulation and Methods of Using the Same |
WO2011057222A1 (en) * | 2009-11-06 | 2011-05-12 | Infinity Pharmaceuticals, Inc. | Oral formulations of a hedgehog pathway inhibitor |
US20110318412A1 (en) * | 2006-05-19 | 2011-12-29 | Somaxon Pharmaceuticals, Inc. | Low dose doxepin formulations, including buccal, sublingual and fastmelt formulations, and uses of the same to treat insomnia |
US8216610B2 (en) | 2004-05-28 | 2012-07-10 | Imaginot Pty Ltd. | Oral paracetamol formulations |
US8293760B2 (en) | 2007-03-07 | 2012-10-23 | Infinity Discovery, Inc. | Cyclopamine lactam analogs and methods of use thereof |
US8426436B2 (en) | 2007-03-07 | 2013-04-23 | Infinity Discovery, Inc. | Heterocyclic cyclopamine analogs and methods of use thereof |
US9238672B2 (en) | 2007-12-27 | 2016-01-19 | Infinity Pharmaceuticals, Inc. | Methods for stereoselective reduction |
US9376447B2 (en) | 2010-09-14 | 2016-06-28 | Infinity Pharmaceuticals, Inc. | Transfer hydrogenation of cyclopamine analogs |
US9532971B2 (en) | 2007-04-13 | 2017-01-03 | Pernix Sleep, Inc. | Low-dose doxepin formulations and methods of making and using the same |
US9879293B2 (en) | 2009-08-05 | 2018-01-30 | Infinity Pharmaceuticals, Inc. | Enzymatic transamination of cyclopamine analogs |
US20180243543A1 (en) * | 2017-02-27 | 2018-08-30 | Quadmedicine | Microneedle and method of manufacturing the same |
US10369147B2 (en) | 2015-06-04 | 2019-08-06 | PellePharm, Inc. | Topical formulations for delivery of hedgehog inhibitor compounds and use thereof |
US11224657B2 (en) | 2017-06-20 | 2022-01-18 | Société des Produits Nestlé S. A. | Orally dissolving melatonin formulation with acidifying agent that renders melatonin soluble in saliva |
US11234954B2 (en) | 2006-05-19 | 2022-02-01 | Currax Pharmaceuticals Llc | Low-dose doxepin for treatment of sleep disorders in elderly patients |
EP2939661B1 (en) * | 2012-12-31 | 2022-11-23 | CorePharm Co., Ltd. | Novel microgranular formulation |
Families Citing this family (61)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP3270761B2 (en) | 1998-01-30 | 2002-04-02 | ノボ ノルディスク アクティーゼルスカブ | Syringe |
TW453884B (en) | 1999-09-16 | 2001-09-11 | Novo Nordisk As | Dose setting limiter |
US6663602B2 (en) | 2000-06-16 | 2003-12-16 | Novo Nordisk A/S | Injection device |
GB0208742D0 (en) | 2002-04-17 | 2002-05-29 | Bradford Particle Design Ltd | Particulate materials |
GB0209526D0 (en) * | 2002-04-26 | 2002-06-05 | Glaxo Group Ltd | Medicament dispenser |
DK1539157T3 (en) | 2002-09-18 | 2013-10-07 | Univ Pennsylvania | METHOD OF INHALING CHOROIDAL NEOVASCULARIZATION |
EP1575448A1 (en) * | 2002-12-19 | 2005-09-21 | Koninklijke Philips Electronics N.V. | Discrete-amount fluid-dispensing system for a personal care device |
GB0304822D0 (en) | 2003-03-03 | 2003-04-09 | Dca Internat Ltd | Improvements in and relating to a pen-type injector |
EP2210634A1 (en) | 2009-01-22 | 2010-07-28 | Sanofi-Aventis Deutschland GmbH | Drug delivery device dose setting mechanism |
GB0308267D0 (en) | 2003-04-10 | 2003-05-14 | Dca Design Int Ltd | Improvements in and relating to a pen-type injector |
US7963201B2 (en) * | 2003-08-26 | 2011-06-21 | Concept Medical Technologies, Inc. | Medication dispensing method and apparatus |
EP1711220A1 (en) * | 2004-01-16 | 2006-10-18 | Biodel, Inc. | Sublingual drug delivery device |
NZ548888A (en) * | 2004-02-16 | 2010-06-25 | Glaxo Group Ltd | Counter for use with a medicament dispenser |
US7384921B2 (en) | 2004-02-20 | 2008-06-10 | Enanta Pharmaceuticals, Inc. | Polymorphic forms of 6-11 bicyclic ketolide derivatives |
US20080096800A1 (en) * | 2004-03-12 | 2008-04-24 | Biodel, Inc. | Rapid mucosal gel or film insulin compositions |
US20080090753A1 (en) | 2004-03-12 | 2008-04-17 | Biodel, Inc. | Rapid Acting Injectable Insulin Compositions |
US20080085298A1 (en) * | 2004-03-12 | 2008-04-10 | Biodel, Inc. | Rapid Mucosal Gel or Film Insulin Compositions |
EP1761250A4 (en) * | 2004-05-28 | 2007-05-09 | Imaginot Pty Ltd | Oral delivery system |
GB0418278D0 (en) | 2004-08-16 | 2004-09-15 | Glaxo Group Ltd | Medicament dispenser |
WO2006045526A1 (en) | 2004-10-21 | 2006-05-04 | Novo Nordisk A/S | Dial-down mechanism for wind-up pen |
GB0501809D0 (en) * | 2005-01-28 | 2005-03-09 | Pharmakodex Ltd | Anti-migraine formulations |
CA2601755C (en) * | 2005-02-03 | 2014-07-29 | Nycomed Pharma As | Melt granulation of a composition containing a calcium-containing compound |
AU2006213673A1 (en) | 2005-02-09 | 2006-08-17 | Santen Pharmaceutical Co., Ltd. | Formulations for ocular treatment |
JP5004236B2 (en) * | 2005-02-09 | 2012-08-22 | キッセイ薬品工業株式会社 | Orally disintegrating tablets |
US20080221530A1 (en) * | 2005-04-24 | 2008-09-11 | Novo Nordisk A/S | Injection Device With A GearBox |
WO2006114396A1 (en) | 2005-04-24 | 2006-11-02 | Novo Nordisk A/S | Injection device |
US8084420B2 (en) * | 2005-09-29 | 2011-12-27 | Biodel Inc. | Rapid acting and long acting insulin combination formulations |
US7713929B2 (en) * | 2006-04-12 | 2010-05-11 | Biodel Inc. | Rapid acting and long acting insulin combination formulations |
JP5528708B2 (en) | 2006-02-09 | 2014-06-25 | 参天製薬株式会社 | Stable formulations and methods for preparing and using them |
US8298194B2 (en) | 2006-03-10 | 2012-10-30 | Novo Nordisk A/S | Injection device and a method of changing a cartridge in the device |
WO2007104697A2 (en) | 2006-03-10 | 2007-09-20 | Novo Nordisk A/S | An injection device having a gearing arrangement |
KR101520408B1 (en) | 2006-03-23 | 2015-05-14 | 산텐 세이야꾸 가부시키가이샤 | Formulations and methods for vascular permeability-related diseases or conditions |
MX2008013165A (en) * | 2006-04-12 | 2009-01-29 | Biodel Inc | Rapid acting and long acting insulin combination formulations. |
US7887757B2 (en) * | 2006-05-09 | 2011-02-15 | Becton, Dickinson And Company | Method and apparatus for dispensing diagnostic test strips |
US8226618B2 (en) | 2006-05-16 | 2012-07-24 | Novo Nordisk A/S | Gearing mechanism for an injection device |
CN101448536B (en) | 2006-05-18 | 2011-09-07 | 诺沃-诺迪斯克有限公司 | An injection device with mode locking means |
US7699191B2 (en) * | 2006-11-09 | 2010-04-20 | Ethicon Endo-Surgery, Inc. | Surgical multiple use adhesive applier |
GB0622827D0 (en) * | 2006-11-15 | 2006-12-27 | Glaxo Group Ltd | Sheet driver for use in a drug dispenser |
WO2008074153A1 (en) | 2006-12-18 | 2008-06-26 | Electronic Dietary Foods Inc. | Device for delivery of a substance |
JP5634068B2 (en) | 2007-02-05 | 2014-12-03 | ノボ・ノルデイスク・エー/エス | Injection button |
EP2120875B1 (en) | 2007-02-11 | 2018-07-11 | Map Pharmaceuticals Inc. | Method of therapeutic administration of dhe to enable rapid relief of migraine while minimizing side effect profile |
JP5301102B2 (en) * | 2007-03-14 | 2013-09-25 | クラシエフーズ株式会社 | Gelling agent swelling inhibitor, jelly food in sealed container with mouthpiece and gelling agent swelling inhibiting method using the same |
EP2125081B1 (en) | 2007-03-23 | 2017-12-20 | Novo Nordisk A/S | An injection device comprising a locking nut |
WO2008124522A2 (en) * | 2007-04-04 | 2008-10-16 | Biodel, Inc. | Amylin formulations |
US20090048155A1 (en) | 2007-08-15 | 2009-02-19 | Endacea, Inc. | Methods for preventing and treating tissue injury and sepsis associated with Yersinia pestis infection |
JP5603248B2 (en) | 2007-12-21 | 2014-10-08 | エンダセア, インコーポレイテッド | A1 adenosine receptor antagonist |
EP2082759A1 (en) * | 2008-01-24 | 2009-07-29 | Boehringer Ingelheim International GmbH | Inhaler |
US8734408B2 (en) * | 2008-02-05 | 2014-05-27 | Alvin J. Marx | Automated eyedrop delivery system with eyelid retracting legs |
US20100032444A1 (en) * | 2008-08-07 | 2010-02-11 | Wanda Sheffield | Dispenser For An Orally Dissolvable Strip |
US9060927B2 (en) * | 2009-03-03 | 2015-06-23 | Biodel Inc. | Insulin formulations for rapid uptake |
US9877967B2 (en) | 2010-01-26 | 2018-01-30 | Endacea, Inc. | Methods and pharmaceutical compositions for preventing and treating renal impairment |
KR101285214B1 (en) | 2011-12-22 | 2013-07-11 | 삼아제약 주식회사 | Novel granule formulation with improved solubility |
MX2014007375A (en) | 2011-12-29 | 2014-08-22 | Novo Nordisk As | Torsion- spring based wind-up autoinjector pen with dial - up/dial - down dosing mechanism. |
AU2016297679B2 (en) * | 2015-07-20 | 2020-10-15 | Medical Developments International Limited | Inhaler device for inhalable liquids |
CA3082033A1 (en) | 2017-08-24 | 2019-02-28 | Novo Nordisk A\S | Glp-1 compositions and uses thereof |
AU2019267308A1 (en) * | 2018-05-08 | 2021-01-07 | Omega Life Science Ltd. | Nebulizers, nebulizer cartridges and uses thereof |
US11410764B1 (en) | 2019-11-15 | 2022-08-09 | Express Scripts Strategic Development, Inc. | Smart medication dispenser |
CN111012665A (en) * | 2020-01-08 | 2020-04-17 | 吉林大学 | Micro-quantity quantitative drawing and dispensing device for injector |
PE20230819A1 (en) | 2020-02-18 | 2023-05-19 | Novo Nordisk As | COMPOSITIONS AND USES OF GLP-1 |
WO2023145870A1 (en) * | 2022-01-31 | 2023-08-03 | 住友精化株式会社 | Formulation composition, formulation, and method for producing formulation composition |
WO2023145868A1 (en) * | 2022-01-31 | 2023-08-03 | 住友精化株式会社 | Composition for formulation, formulation and method for manufacturing composition for formulation |
Citations (31)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3887700A (en) * | 1969-11-28 | 1975-06-03 | Aspro Nicholas Ltd | Analgesic formulations |
US4371516A (en) * | 1976-10-06 | 1983-02-01 | John Wyeth & Brother Limited | Articles for carrying chemicals |
US4855326A (en) * | 1987-04-20 | 1989-08-08 | Fuisz Pharmaceutical Ltd. | Rapidly dissoluble medicinal dosage unit and method of manufacture |
US5069910A (en) * | 1988-06-23 | 1991-12-03 | Lek | Dispersible cimetidine tablets |
US5073377A (en) * | 1988-11-03 | 1991-12-17 | Miles Inc. | Method of preparing oral dosage forms with a granulating composition |
US5178878A (en) * | 1989-10-02 | 1993-01-12 | Cima Labs, Inc. | Effervescent dosage form with microparticles |
US5223264A (en) * | 1989-10-02 | 1993-06-29 | Cima Labs, Inc. | Pediatric effervescent dosage form |
US5244670A (en) * | 1991-04-04 | 1993-09-14 | The Procter & Gamble Company | Ingestible pharmaceutical compositions for treating upper gastrointestinal tract distress |
US5254330A (en) * | 1990-01-24 | 1993-10-19 | British Technology Group Ltd. | Aerosol carriers |
US5302396A (en) * | 1990-09-21 | 1994-04-12 | Merrell Dow Pharmaceuticals Inc. | Superior tasting composition having porous particles and the process of preparing such pharmaceutical composition |
US5320848A (en) * | 1991-05-28 | 1994-06-14 | Affinity Biotech, Inc. | Chewable drug-delivery composition |
US5320852A (en) * | 1989-11-10 | 1994-06-14 | Nordmark Arzneimittel Gmbh | Antacid microtablets |
US5348745A (en) * | 1989-05-09 | 1994-09-20 | Miles Inc. | Aqueous granulation solution and a method of tablet granulation |
US5494681A (en) * | 1992-11-30 | 1996-02-27 | Kv Pharmaceutical Company | Tastemasked pharmaceutical materials |
US5496563A (en) * | 1991-08-30 | 1996-03-05 | Showa Yakuhin Kako Co., Ltd. | Dry gel composition |
US5503846A (en) * | 1993-03-17 | 1996-04-02 | Cima Labs, Inc. | Base coated acid particles and effervescent formulation incorporating same |
US5562919A (en) * | 1993-05-20 | 1996-10-08 | American Meat Protein Corporation | Dried animal plasma as a pharmaceutical excipient for compressed tablet formulation |
US5576014A (en) * | 1994-01-31 | 1996-11-19 | Yamanouchi Pharmaceutical Co., Ltd | Intrabuccally dissolving compressed moldings and production process thereof |
US5605889A (en) * | 1994-04-29 | 1997-02-25 | Pfizer Inc. | Method of administering azithromycin |
US5607697A (en) * | 1995-06-07 | 1997-03-04 | Cima Labs, Incorporated | Taste masking microparticles for oral dosage forms |
US5733577A (en) * | 1994-06-14 | 1998-03-31 | Fuisz Technologies Ltd. | Delivery of controlled-release system (s) |
US5807578A (en) * | 1995-11-22 | 1998-09-15 | Lab Pharmaceutical Research International Inc. | Fast-melt tablet and method of making same |
US5807577A (en) * | 1995-11-22 | 1998-09-15 | Lab Pharmaceutical Research International Inc. | Fast-melt tablet and method of making same |
US5939091A (en) * | 1997-05-20 | 1999-08-17 | Warner Lambert Company | Method for making fast-melt tablets |
US6024981A (en) * | 1997-04-16 | 2000-02-15 | Cima Labs Inc. | Rapidly dissolving robust dosage form |
US6139865A (en) * | 1996-10-01 | 2000-10-31 | Eurand America, Inc. | Taste-masked microcapsule compositions and methods of manufacture |
US6228398B1 (en) * | 1998-11-02 | 2001-05-08 | Elan Corporation, Plc | Multiparticulate modified release composition |
US6316029B1 (en) * | 2000-05-18 | 2001-11-13 | Flak Pharma International, Ltd. | Rapidly disintegrating solid oral dosage form |
US6328994B1 (en) * | 1998-05-18 | 2001-12-11 | Takeda Chemical Industries, Ltd. | Orally disintegrable tablets |
US6475510B1 (en) * | 1997-12-19 | 2002-11-05 | Smithkline Beecham Corporation | Process for manufacturing bite-dispersion tablets |
US6488961B1 (en) * | 1996-09-20 | 2002-12-03 | Ethypharm, Inc. | Effervescent granules and methods for their preparation |
Family Cites Families (32)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3482733A (en) * | 1965-10-01 | 1969-12-09 | Robert C Groves | Strip package |
US3410450A (en) * | 1967-06-16 | 1968-11-12 | Jerry A. Fortenberry | Sanitary pill dispenser with indicator |
BE759520A (en) * | 1969-11-28 | 1971-04-30 | Aspro Nicholas Ltd | ASPIRIN COMPOSITIONS |
GB1518998A (en) * | 1975-08-28 | 1978-07-26 | Gillette Co | Packaging flowable materials |
DE3268533D1 (en) | 1981-07-24 | 1986-02-27 | Fisons Plc | Inhalation drugs, methods for their production and pharmaceutical formulations containing them |
FI69963C (en) | 1984-10-04 | 1986-09-12 | Orion Yhtymae Oy | DOSERINGSANORDNING |
US4733797A (en) * | 1986-09-22 | 1988-03-29 | Haber Terry M | Dosage sealing, monitoring and dispensing assembly |
JP3078859B2 (en) * | 1990-02-23 | 2000-08-21 | 武田薬品工業株式会社 | Coating agent for stable controlled release formulation |
GB9004781D0 (en) * | 1990-03-02 | 1990-04-25 | Glaxo Group Ltd | Device |
IT1243344B (en) | 1990-07-16 | 1994-06-10 | Promo Pack Sa | MULTI-DOSE INHALER FOR POWDER MEDICATIONS |
GB9026025D0 (en) | 1990-11-29 | 1991-01-16 | Boehringer Ingelheim Kg | Inhalation device |
AU650953B2 (en) | 1991-03-21 | 1994-07-07 | Novartis Ag | Inhaler |
DE69332240T2 (en) | 1992-06-12 | 2003-04-10 | Teijin Ltd | ULTRA FINE POWDER FOR INHALATION AND PRODUCTION |
GB2269992A (en) | 1992-08-14 | 1994-03-02 | Rh Ne Poulenc Rorer Limited | Powder inhalation formulations |
US5497763A (en) * | 1993-05-21 | 1996-03-12 | Aradigm Corporation | Disposable package for intrapulmonary delivery of aerosolized formulations |
DE4340768A1 (en) | 1993-11-30 | 1995-06-01 | Bayer Ag | Inhalation device |
US5483954A (en) | 1994-06-10 | 1996-01-16 | Mecikalski; Mark B. | Inhaler and medicated package |
GB9417399D0 (en) * | 1994-08-30 | 1994-10-19 | Scherer Corp R P | Ocular treatment device |
GB9501841D0 (en) | 1995-01-31 | 1995-03-22 | Co Ordinated Drug Dev | Improvements in and relating to carrier particles for use in dry powder inhalers |
GB9502794D0 (en) * | 1995-02-14 | 1995-04-05 | Cerestar Holding Bv | Chocolate composition |
DE19518810A1 (en) | 1995-05-26 | 1996-11-28 | Bayer Ag | Nasal applicator |
US6192882B1 (en) * | 1997-02-24 | 2001-02-27 | Aradigm Corporation | Formulation and devices for monitoring the efficacy of the delivery of aerosols |
US5829435A (en) * | 1997-02-24 | 1998-11-03 | Aradigm Corporation | Prefilter for prevention of clogging of a nozzle in the generation of an aerosol and prevention of administration of undesirable particles |
US5881720A (en) | 1997-04-29 | 1999-03-16 | The Procter & Gamble Company | Method of delivering halotherapy |
GB9811606D0 (en) * | 1998-05-30 | 1998-07-29 | Cerestar Holding Bv | Liquid products containing erythritol |
FI107126B (en) | 1999-04-23 | 2001-06-15 | Orion Yhtymae Oyj | Powder inhaler for combination medicine |
EP1220658A1 (en) * | 1999-09-28 | 2002-07-10 | H. Lundbeck A/S | Melt granulated composition and modified release dosage form prepared from said composition |
EP1941868A3 (en) | 2000-02-28 | 2011-06-29 | PharmaKodex Limited | Improvements in or relating to the delivery of oral drugs |
ATE334659T1 (en) * | 2000-03-08 | 2006-08-15 | Awd Pharma Gmbh & Co Kg | PHARMACEUTICAL FORMULATIONS CONTAINING SUCROSE FATTY ACID ESTERS FOR CONTROLLING THE RELEASE OF ACTIVE INGREDIENTS |
US20020119196A1 (en) * | 2000-12-21 | 2002-08-29 | Narendra Parikh | Texture masked particles containing an active ingredient |
EP1423092A2 (en) | 2001-09-05 | 2004-06-02 | Vectura Limited | Functional powders for oral delivery |
JP2005527508A (en) | 2002-03-07 | 2005-09-15 | ヴェクトゥラ リミテッド | Rapid melting multiparticulate formulation for oral delivery |
-
2003
- 2003-03-07 JP JP2003572549A patent/JP2005527508A/en active Pending
- 2003-03-07 US US10/383,408 patent/US6941948B2/en not_active Expired - Fee Related
- 2003-03-07 EP EP03743448A patent/EP1490031A1/en not_active Withdrawn
- 2003-03-07 WO PCT/GB2003/000969 patent/WO2003074029A1/en active Application Filing
- 2003-03-07 US US10/383,351 patent/US20030175355A1/en not_active Abandoned
- 2003-03-07 AU AU2003209475A patent/AU2003209475A1/en not_active Abandoned
-
2005
- 2005-04-27 US US11/115,826 patent/US20050205083A1/en not_active Abandoned
Patent Citations (31)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3887700A (en) * | 1969-11-28 | 1975-06-03 | Aspro Nicholas Ltd | Analgesic formulations |
US4371516A (en) * | 1976-10-06 | 1983-02-01 | John Wyeth & Brother Limited | Articles for carrying chemicals |
US4855326A (en) * | 1987-04-20 | 1989-08-08 | Fuisz Pharmaceutical Ltd. | Rapidly dissoluble medicinal dosage unit and method of manufacture |
US5069910A (en) * | 1988-06-23 | 1991-12-03 | Lek | Dispersible cimetidine tablets |
US5073377A (en) * | 1988-11-03 | 1991-12-17 | Miles Inc. | Method of preparing oral dosage forms with a granulating composition |
US5348745A (en) * | 1989-05-09 | 1994-09-20 | Miles Inc. | Aqueous granulation solution and a method of tablet granulation |
US5223264A (en) * | 1989-10-02 | 1993-06-29 | Cima Labs, Inc. | Pediatric effervescent dosage form |
US5178878A (en) * | 1989-10-02 | 1993-01-12 | Cima Labs, Inc. | Effervescent dosage form with microparticles |
US5320852A (en) * | 1989-11-10 | 1994-06-14 | Nordmark Arzneimittel Gmbh | Antacid microtablets |
US5254330A (en) * | 1990-01-24 | 1993-10-19 | British Technology Group Ltd. | Aerosol carriers |
US5302396A (en) * | 1990-09-21 | 1994-04-12 | Merrell Dow Pharmaceuticals Inc. | Superior tasting composition having porous particles and the process of preparing such pharmaceutical composition |
US5244670A (en) * | 1991-04-04 | 1993-09-14 | The Procter & Gamble Company | Ingestible pharmaceutical compositions for treating upper gastrointestinal tract distress |
US5320848A (en) * | 1991-05-28 | 1994-06-14 | Affinity Biotech, Inc. | Chewable drug-delivery composition |
US5496563A (en) * | 1991-08-30 | 1996-03-05 | Showa Yakuhin Kako Co., Ltd. | Dry gel composition |
US5494681A (en) * | 1992-11-30 | 1996-02-27 | Kv Pharmaceutical Company | Tastemasked pharmaceutical materials |
US5503846A (en) * | 1993-03-17 | 1996-04-02 | Cima Labs, Inc. | Base coated acid particles and effervescent formulation incorporating same |
US5562919A (en) * | 1993-05-20 | 1996-10-08 | American Meat Protein Corporation | Dried animal plasma as a pharmaceutical excipient for compressed tablet formulation |
US5576014A (en) * | 1994-01-31 | 1996-11-19 | Yamanouchi Pharmaceutical Co., Ltd | Intrabuccally dissolving compressed moldings and production process thereof |
US5605889A (en) * | 1994-04-29 | 1997-02-25 | Pfizer Inc. | Method of administering azithromycin |
US5733577A (en) * | 1994-06-14 | 1998-03-31 | Fuisz Technologies Ltd. | Delivery of controlled-release system (s) |
US5607697A (en) * | 1995-06-07 | 1997-03-04 | Cima Labs, Incorporated | Taste masking microparticles for oral dosage forms |
US5807577A (en) * | 1995-11-22 | 1998-09-15 | Lab Pharmaceutical Research International Inc. | Fast-melt tablet and method of making same |
US5807578A (en) * | 1995-11-22 | 1998-09-15 | Lab Pharmaceutical Research International Inc. | Fast-melt tablet and method of making same |
US6488961B1 (en) * | 1996-09-20 | 2002-12-03 | Ethypharm, Inc. | Effervescent granules and methods for their preparation |
US6139865A (en) * | 1996-10-01 | 2000-10-31 | Eurand America, Inc. | Taste-masked microcapsule compositions and methods of manufacture |
US6024981A (en) * | 1997-04-16 | 2000-02-15 | Cima Labs Inc. | Rapidly dissolving robust dosage form |
US5939091A (en) * | 1997-05-20 | 1999-08-17 | Warner Lambert Company | Method for making fast-melt tablets |
US6475510B1 (en) * | 1997-12-19 | 2002-11-05 | Smithkline Beecham Corporation | Process for manufacturing bite-dispersion tablets |
US6328994B1 (en) * | 1998-05-18 | 2001-12-11 | Takeda Chemical Industries, Ltd. | Orally disintegrable tablets |
US6228398B1 (en) * | 1998-11-02 | 2001-05-08 | Elan Corporation, Plc | Multiparticulate modified release composition |
US6316029B1 (en) * | 2000-05-18 | 2001-11-13 | Flak Pharma International, Ltd. | Rapidly disintegrating solid oral dosage form |
Cited By (61)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6941948B2 (en) | 2002-03-07 | 2005-09-13 | Vectura Drug Delivery | Medicament storage and delivery devices |
US20040228804A1 (en) * | 2003-05-16 | 2004-11-18 | Jones Alonzo H. | Nasal administration of xylitol to a non-human mammal |
WO2005063203A2 (en) * | 2003-12-31 | 2005-07-14 | Vectura Ltd | Multiparticulate formulations for oral delivery |
WO2005063203A3 (en) * | 2003-12-31 | 2005-12-01 | Vectura Ltd | Multiparticulate formulations for oral delivery |
US20070154549A1 (en) * | 2003-12-31 | 2007-07-05 | Vectura Ltd | Multiparticulate formulations for oral delivery |
US20080287456A1 (en) * | 2004-05-28 | 2008-11-20 | Imaginot Pty Ltd | Oral Therapeutic Compound Delivery System |
US8216610B2 (en) | 2004-05-28 | 2012-07-10 | Imaginot Pty Ltd. | Oral paracetamol formulations |
US9642800B2 (en) | 2004-11-23 | 2017-05-09 | Vectura Limited | Dry powder inhaler formulations comprising surface-modified particles with anti-adherent additives |
US9585834B2 (en) | 2004-11-23 | 2017-03-07 | Vectura Limited | Dry powder inhaler formulations comprising surface-modified particles with anti-adherent additives |
US20080127972A1 (en) * | 2004-11-23 | 2008-06-05 | Vectura Limited | Dry Powder Inhaler Formulations Comprising Surface-Modified Particles With Anti-Adherent Additives |
US20110236492A1 (en) * | 2004-11-23 | 2011-09-29 | Vectura Limited | Dry powder inhaler formulations comprising surface-modified particles with anti-adherent additives |
US20080220078A1 (en) * | 2004-11-30 | 2008-09-11 | Vectura Limited | Pharmaceutical Formulations |
EP1868583A4 (en) * | 2005-04-12 | 2011-03-02 | Elan Pharma Int Ltd | Controlled release compositions comprising a cephalosporin for the treatment of a bacterial infection |
EP1868583A1 (en) * | 2005-04-12 | 2007-12-26 | Elan Pharma International Limited | Controlled release compositions comprising a cephalosporin for the treatment of a bacterial infection |
WO2006131806A3 (en) * | 2005-06-07 | 2007-04-12 | Pfizer Prod Inc | Multiparticulates comprising low-solubility drugs and carriers that result in rapid drug release |
WO2006131806A2 (en) * | 2005-06-07 | 2006-12-14 | Pfizer Products Inc. | Multiparticulates comprising low-solubility drugs and carriers that result in rapid drug release |
US20090311327A1 (en) * | 2005-11-28 | 2009-12-17 | Imaginot Pty Ltd | Oral Therapeutic Compound Delivery System |
US9757455B2 (en) | 2005-11-28 | 2017-09-12 | Johnson & Johnson Consumer Inc. | Oral therapeutic compound delivery system |
US11234954B2 (en) | 2006-05-19 | 2022-02-01 | Currax Pharmaceuticals Llc | Low-dose doxepin for treatment of sleep disorders in elderly patients |
US20110318412A1 (en) * | 2006-05-19 | 2011-12-29 | Somaxon Pharmaceuticals, Inc. | Low dose doxepin formulations, including buccal, sublingual and fastmelt formulations, and uses of the same to treat insomnia |
US20090317460A1 (en) * | 2006-08-24 | 2009-12-24 | Arrow International Limited | Solid dosage form |
US10420725B2 (en) | 2006-08-24 | 2019-09-24 | Allergan Pharmaceuticals International Limited | Solid dosage form of coated bisphosphonate particles |
WO2008023184A3 (en) * | 2006-08-24 | 2008-04-24 | Arrow Int Ltd | Solid dosage form |
US8697124B2 (en) | 2006-08-24 | 2014-04-15 | Arrow International Limited | Solid dosage form of coated bisphosphonate particles |
US9145422B2 (en) | 2006-12-28 | 2015-09-29 | Infinity Pharmaceuticals, Inc. | Methods of use of cyclopamine analogs |
US9951083B2 (en) | 2006-12-28 | 2018-04-24 | Infinity Pharmaceuticals, Inc. | Cyclopamine analogs |
US11602527B2 (en) | 2006-12-28 | 2023-03-14 | Infinity Pharmaceuticals, Inc. | Methods of use of cyclopamine analogs |
US20090012109A1 (en) * | 2006-12-28 | 2009-01-08 | Brian Austad | Cyclopamine analogs |
US8785635B2 (en) | 2006-12-28 | 2014-07-22 | Infinity Pharmaceuticals, Inc. | Cyclopamine analogs |
US8895576B2 (en) | 2006-12-28 | 2014-11-25 | Infinity Pharmaceuticals, Inc. | Methods of use of cyclopamine analogs |
US8227509B2 (en) | 2006-12-28 | 2012-07-24 | Infinity Pharmaceuticals, Inc. | Methods of use of cyclopamine analogs |
US11007181B2 (en) | 2006-12-28 | 2021-05-18 | Infinity Pharmaceuticals, Inc. | Cyclopamine analogs |
US10821102B2 (en) | 2006-12-28 | 2020-11-03 | Infinity Pharmaceuticals, Inc. | Methods of use of cyclopamine analogs |
US10406139B2 (en) | 2006-12-28 | 2019-09-10 | Infinity Pharmaceuticals, Inc. | Cyclopamine analogs |
US9492435B2 (en) | 2006-12-28 | 2016-11-15 | Infinity Pharmaceuticals, Inc. | Cyclopamine analogs |
US10314827B2 (en) | 2006-12-28 | 2019-06-11 | Infinity Pharmaceuticals, Inc. | Methods of use of cyclopamine analogs |
US20110230509A1 (en) * | 2006-12-28 | 2011-09-22 | Castro Alfredo C | Methods of use for cyclopamine analogs |
US10045970B2 (en) | 2006-12-28 | 2018-08-14 | Infinity Pharmaceuticals, Inc. | Methods of use of cyclopamine analogs |
US9669011B2 (en) | 2006-12-28 | 2017-06-06 | Infinity Pharmaceuticals, Inc. | Methods of use of cyclopamine analogs |
US8431566B2 (en) | 2007-03-07 | 2013-04-30 | Infinity Discovery, Inc. | Cyclopamine lactam analogs and methods of use thereof |
US8426436B2 (en) | 2007-03-07 | 2013-04-23 | Infinity Discovery, Inc. | Heterocyclic cyclopamine analogs and methods of use thereof |
US8293760B2 (en) | 2007-03-07 | 2012-10-23 | Infinity Discovery, Inc. | Cyclopamine lactam analogs and methods of use thereof |
US9907780B2 (en) | 2007-04-13 | 2018-03-06 | Pernix Sleep, Inc. | Low-dose doxepin formulations and methods of making and using the same |
US11096920B2 (en) | 2007-04-13 | 2021-08-24 | Currax Pharmaceuticals Llc | Low-dose doxepin formulations and methods of making and using the same |
US9532971B2 (en) | 2007-04-13 | 2017-01-03 | Pernix Sleep, Inc. | Low-dose doxepin formulations and methods of making and using the same |
US9238672B2 (en) | 2007-12-27 | 2016-01-19 | Infinity Pharmaceuticals, Inc. | Methods for stereoselective reduction |
US20100190739A1 (en) * | 2008-12-15 | 2010-07-29 | Fleming And Company, Pharmaceuticals | Rapidly Dissolving Vitamin Formulation and Methods of Using the Same |
US9879293B2 (en) | 2009-08-05 | 2018-01-30 | Infinity Pharmaceuticals, Inc. | Enzymatic transamination of cyclopamine analogs |
US20110135739A1 (en) * | 2009-11-06 | 2011-06-09 | Bennett Carter | Oral Formulations of a Hedgehog Pathway Inhibitor |
WO2011057222A1 (en) * | 2009-11-06 | 2011-05-12 | Infinity Pharmaceuticals, Inc. | Oral formulations of a hedgehog pathway inhibitor |
US9394313B2 (en) | 2010-09-14 | 2016-07-19 | Infinity Pharmaceuticals, Inc. | Transfer hydrogenation of cyclopamine analogs |
US9376447B2 (en) | 2010-09-14 | 2016-06-28 | Infinity Pharmaceuticals, Inc. | Transfer hydrogenation of cyclopamine analogs |
US9879025B2 (en) | 2010-09-14 | 2018-01-30 | Infinity Pharmaceuticals, Inc. | Transfer hydrogenation of cyclopamine analogs |
EP2939661B1 (en) * | 2012-12-31 | 2022-11-23 | CorePharm Co., Ltd. | Novel microgranular formulation |
US10695344B2 (en) | 2015-06-04 | 2020-06-30 | PellePharm, Inc. | Topical formulations for delivery of hedgehog inhibitor compounds and use thereof |
US10369147B2 (en) | 2015-06-04 | 2019-08-06 | PellePharm, Inc. | Topical formulations for delivery of hedgehog inhibitor compounds and use thereof |
US11413283B2 (en) | 2015-06-04 | 2022-08-16 | PellePharm, Inc. | Topical formulations for delivery of hedgehog inhibitor compounds and use thereof |
US20180243543A1 (en) * | 2017-02-27 | 2018-08-30 | Quadmedicine | Microneedle and method of manufacturing the same |
US11213663B2 (en) * | 2017-02-27 | 2022-01-04 | Quadmedicine | Microneedle and method of manufacturing the same |
US11224657B2 (en) | 2017-06-20 | 2022-01-18 | Société des Produits Nestlé S. A. | Orally dissolving melatonin formulation with acidifying agent that renders melatonin soluble in saliva |
US11224658B2 (en) * | 2017-06-20 | 2022-01-18 | Société des Produits Nestlé S.A. | Orally dissolving melatonin formulation with acidifying agent that renders melatonin soluble in saliva |
Also Published As
Publication number | Publication date |
---|---|
US20050205083A1 (en) | 2005-09-22 |
WO2003074029A1 (en) | 2003-09-12 |
US6941948B2 (en) | 2005-09-13 |
JP2005527508A (en) | 2005-09-15 |
US20030172924A1 (en) | 2003-09-18 |
EP1490031A1 (en) | 2004-12-29 |
AU2003209475A1 (en) | 2003-09-16 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20030175355A1 (en) | Fast melt multiparticulate formulations for oral delivery | |
US20050013862A1 (en) | Functional powders for oral delivery | |
US20070154549A1 (en) | Multiparticulate formulations for oral delivery | |
AU2005237411C1 (en) | Orally disintegrating tablets and methods of manufacture | |
AU639334B2 (en) | Taste masking and sustained release coatings for pharmaceuticals | |
CN100544705C (en) | The texture screening granules that contains active component | |
IE902823A1 (en) | Rotogranulations and taste masking coatings for preparation of chewable pharmaceutical tablets | |
JP2003520223A (en) | Multi-spike release formulation for drug delivery | |
US20130071476A1 (en) | Rapid Melt Controlled Release Taste-Masked Compositions | |
WO2015034678A2 (en) | Corticosteroid containing orally disintegrating tablet compositions for eosinophilic esophagitis | |
JP2002514212A (en) | Cefadroxyl monohydrate tablet formulation | |
BR112021016485A2 (en) | MINIMIZATION OF AGLOMERATION OF PHARMACEUTICAL PARTICLE COATING MATERIAL DURING STORAGE TO STABILIZE PHARMACEUTICAL PRODUCT DISINTEGRATION TIMES | |
US20130203721A1 (en) | Taste-masked powder for suspension compositions of methylprednisolone | |
JP4716063B2 (en) | Unpleasant taste masking particles and oral preparations containing the same | |
WO2005011637A1 (en) | At-use dispersed preparation | |
WO1996021432A1 (en) | Delivery of active substances by way of mucosal surfaces of pharyngeal and esophageal regions | |
TW200526270A (en) | Controlled release dosage forms of azithromycin | |
JP7182550B2 (en) | Pharmaceutical composition particles, orally disintegrating preparation containing same, and method for producing pharmaceutical composition particles | |
US20230248654A1 (en) | Swellable oral pharmaceutical compositions | |
Kataria et al. | FAST DISSOLVING TABLETS: AN OVERVIEW |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: VECTURA DRUG DELIVERY, UNITED KINGDOM Free format text: CHANGE OF NAME;ASSIGNORS:TOBYN, MICHAEL JOHN;STANIFORTH, JOHN NICHOLAS;SIMPSON, DAVID BRADLEY BROOK;AND OTHERS;REEL/FRAME:013950/0053;SIGNING DATES FROM 20030324 TO 20030402 |
|
AS | Assignment |
Owner name: PHARMAKODEX LIMITED, UNITED KINGDOM Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:VECTURA LIMITED;REEL/FRAME:022262/0771 Effective date: 20090209 |
|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |