EP3288518A1 - Dual-chamber pack for extended release suspension compositions - Google Patents
Dual-chamber pack for extended release suspension compositionsInfo
- Publication number
- EP3288518A1 EP3288518A1 EP16789381.7A EP16789381A EP3288518A1 EP 3288518 A1 EP3288518 A1 EP 3288518A1 EP 16789381 A EP16789381 A EP 16789381A EP 3288518 A1 EP3288518 A1 EP 3288518A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- chamber
- suspension
- dual
- plunger
- pack
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 84
- 229940102215 extended release suspension Drugs 0.000 title claims abstract description 33
- 239000000725 suspension Substances 0.000 claims abstract description 126
- 239000004480 active ingredient Substances 0.000 claims abstract description 75
- 239000000843 powder Substances 0.000 claims abstract description 68
- 238000000338 in vitro Methods 0.000 claims abstract description 29
- 230000004913 activation Effects 0.000 claims abstract description 18
- 238000004090 dissolution Methods 0.000 claims abstract description 17
- 230000008859 change Effects 0.000 claims abstract description 12
- -1 faraglitazar Chemical compound 0.000 claims description 39
- 238000013265 extended release Methods 0.000 claims description 34
- 239000012528 membrane Substances 0.000 claims description 31
- 230000009977 dual effect Effects 0.000 claims description 28
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 claims description 21
- 230000004888 barrier function Effects 0.000 claims description 20
- 239000003795 chemical substances by application Substances 0.000 claims description 19
- 229920003134 Eudragit® polymer Polymers 0.000 claims description 18
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 claims description 18
- 230000002051 biphasic effect Effects 0.000 claims description 18
- 239000000654 additive Substances 0.000 claims description 16
- 229960003105 metformin Drugs 0.000 claims description 14
- 229920001577 copolymer Polymers 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 11
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 10
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 claims description 8
- 239000000375 suspending agent Substances 0.000 claims description 8
- 229920002554 vinyl polymer Polymers 0.000 claims description 7
- 229920001285 xanthan gum Polymers 0.000 claims description 7
- 235000010493 xanthan gum Nutrition 0.000 claims description 7
- 239000000230 xanthan gum Substances 0.000 claims description 7
- 229940082509 xanthan gum Drugs 0.000 claims description 7
- 229920000084 Gum arabic Polymers 0.000 claims description 6
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 claims description 6
- 239000004698 Polyethylene Substances 0.000 claims description 6
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 6
- 235000010489 acacia gum Nutrition 0.000 claims description 6
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 6
- 229920002301 cellulose acetate Polymers 0.000 claims description 6
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 6
- 239000000194 fatty acid Substances 0.000 claims description 6
- 229930195729 fatty acid Natural products 0.000 claims description 6
- 239000000796 flavoring agent Substances 0.000 claims description 6
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 6
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 6
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 6
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 6
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 claims description 6
- 229920000573 polyethylene Polymers 0.000 claims description 6
- 244000215068 Acacia senegal Species 0.000 claims description 5
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 5
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 5
- 239000011247 coating layer Substances 0.000 claims description 5
- 230000001419 dependent effect Effects 0.000 claims description 5
- 229920001223 polyethylene glycol Polymers 0.000 claims description 5
- 229920002689 polyvinyl acetate Polymers 0.000 claims description 5
- 239000011118 polyvinyl acetate Substances 0.000 claims description 5
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 5
- 229920002126 Acrylic acid copolymer Polymers 0.000 claims description 4
- SOGAXMICEFXMKE-UHFFFAOYSA-N Butylmethacrylate Chemical compound CCCCOC(=O)C(C)=C SOGAXMICEFXMKE-UHFFFAOYSA-N 0.000 claims description 4
- 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 4
- 239000001856 Ethyl cellulose Substances 0.000 claims description 4
- 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 4
- UGJMXCAKCUNAIE-UHFFFAOYSA-N Gabapentin Chemical compound OC(=O)CC1(CN)CCCCC1 UGJMXCAKCUNAIE-UHFFFAOYSA-N 0.000 claims description 4
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 claims description 4
- YASAKCUCGLMORW-UHFFFAOYSA-N Rosiglitazone Chemical compound C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O YASAKCUCGLMORW-UHFFFAOYSA-N 0.000 claims description 4
- 239000000205 acacia gum Substances 0.000 claims description 4
- IYKJEILNJZQJPU-UHFFFAOYSA-N acetic acid;butanedioic acid Chemical class CC(O)=O.OC(=O)CCC(O)=O IYKJEILNJZQJPU-UHFFFAOYSA-N 0.000 claims description 4
- 229920006243 acrylic copolymer Polymers 0.000 claims description 4
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 claims description 4
- WHBIGIKBNXZKFE-UHFFFAOYSA-N delavirdine Chemical compound CC(C)NC1=CC=CN=C1N1CCN(C(=O)C=2NC3=CC=C(NS(C)(=O)=O)C=C3C=2)CC1 WHBIGIKBNXZKFE-UHFFFAOYSA-N 0.000 claims description 4
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 4
- 229920001249 ethyl cellulose Polymers 0.000 claims description 4
- 229920013821 hydroxy alkyl cellulose Polymers 0.000 claims description 4
- 229920003145 methacrylic acid copolymer Polymers 0.000 claims description 4
- 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 claims description 4
- HYAFETHFCAUJAY-UHFFFAOYSA-N pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 claims description 4
- LOUPRKONTZGTKE-LHHVKLHASA-N quinidine Chemical compound 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 LOUPRKONTZGTKE-LHHVKLHASA-N 0.000 claims description 4
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 claims description 4
- MSRILKIQRXUYCT-UHFFFAOYSA-M valproate semisodium Chemical compound [Na+].CCCC(C(O)=O)CCC.CCCC(C([O-])=O)CCC MSRILKIQRXUYCT-UHFFFAOYSA-M 0.000 claims description 4
- 229960000604 valproic acid Drugs 0.000 claims description 4
- 239000000080 wetting agent Substances 0.000 claims description 4
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 claims description 3
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 3
- 239000001692 EU approved anti-caking agent Substances 0.000 claims description 3
- 229920002148 Gellan gum Polymers 0.000 claims description 3
- 229920002907 Guar gum Polymers 0.000 claims description 3
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims description 3
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims description 3
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 3
- 229920000161 Locust bean gum Polymers 0.000 claims description 3
- 239000002202 Polyethylene glycol Substances 0.000 claims description 3
- 229920001615 Tragacanth Polymers 0.000 claims description 3
- 239000003963 antioxidant agent Substances 0.000 claims description 3
- 235000006708 antioxidants Nutrition 0.000 claims description 3
- 239000006172 buffering agent Substances 0.000 claims description 3
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 3
- 239000008112 carboxymethyl-cellulose Substances 0.000 claims description 3
- 229940105329 carboxymethylcellulose Drugs 0.000 claims description 3
- 235000010418 carrageenan Nutrition 0.000 claims description 3
- 229920001525 carrageenan Polymers 0.000 claims description 3
- 239000000679 carrageenan Substances 0.000 claims description 3
- 229940113118 carrageenan Drugs 0.000 claims description 3
- 239000002738 chelating agent Substances 0.000 claims description 3
- 235000013355 food flavoring agent Nutrition 0.000 claims description 3
- 235000003599 food sweetener Nutrition 0.000 claims description 3
- 235000010492 gellan gum Nutrition 0.000 claims description 3
- 239000000216 gellan gum Substances 0.000 claims description 3
- 235000010417 guar gum Nutrition 0.000 claims description 3
- 239000000665 guar gum Substances 0.000 claims description 3
- 229960002154 guar gum Drugs 0.000 claims description 3
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims description 3
- 229940071826 hydroxyethyl cellulose Drugs 0.000 claims description 3
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 3
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 3
- 235000010420 locust bean gum Nutrition 0.000 claims description 3
- 239000000711 locust bean gum Substances 0.000 claims description 3
- 229920000609 methyl cellulose Polymers 0.000 claims description 3
- 235000010981 methylcellulose Nutrition 0.000 claims description 3
- 239000001923 methylcellulose Substances 0.000 claims description 3
- 229920000642 polymer Polymers 0.000 claims description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 3
- 239000001103 potassium chloride Substances 0.000 claims description 3
- 235000011164 potassium chloride Nutrition 0.000 claims description 3
- 239000003755 preservative agent Substances 0.000 claims description 3
- 239000003765 sweetening agent Substances 0.000 claims description 3
- 239000001993 wax Substances 0.000 claims description 3
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 claims description 3
- XUFXOAAUWZOOIT-SXARVLRPSA-N (2R,3R,4R,5S,6R)-5-[[(2R,3R,4R,5S,6R)-5-[[(2R,3R,4S,5S,6R)-3,4-dihydroxy-6-methyl-5-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)-1-cyclohex-2-enyl]amino]-2-oxanyl]oxy]-3,4-dihydroxy-6-(hydroxymethyl)-2-oxanyl]oxy]-6-(hydroxymethyl)oxane-2,3,4-triol Chemical compound O([C@H]1O[C@H](CO)[C@H]([C@@H]([C@H]1O)O)O[C@H]1O[C@@H]([C@H]([C@H](O)[C@H]1O)N[C@@H]1[C@@H]([C@@H](O)[C@H](O)C(CO)=C1)O)C)[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O XUFXOAAUWZOOIT-SXARVLRPSA-N 0.000 claims description 2
- BUJAGSGYPOAWEI-SECBINFHSA-N (2r)-2-amino-n-(2,6-dimethylphenyl)propanamide Chemical compound C[C@@H](N)C(=O)NC1=C(C)C=CC=C1C BUJAGSGYPOAWEI-SECBINFHSA-N 0.000 claims description 2
- 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 claims description 2
- LJRDOKAZOAKLDU-UDXJMMFXSA-N (2s,3s,4r,5r,6r)-5-amino-2-(aminomethyl)-6-[(2r,3s,4r,5s)-5-[(1r,2r,3s,5r,6s)-3,5-diamino-2-[(2s,3r,4r,5s,6r)-3-amino-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-6-hydroxycyclohexyl]oxy-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl]oxyoxane-3,4-diol;sulfuric ac Chemical compound OS(O)(=O)=O.N[C@@H]1[C@@H](O)[C@H](O)[C@H](CN)O[C@@H]1O[C@H]1[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](N)C[C@@H](N)[C@@H]2O)O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)N)O[C@@H]1CO LJRDOKAZOAKLDU-UDXJMMFXSA-N 0.000 claims description 2
- OAPVUSSHCBRCOL-KBHRXELFSA-N (4s,4as,5as,6s,12ar)-7-chloro-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide;hydrochloride Chemical compound Cl.C1([C@H]2O)=C(Cl)C=CC(O)=C1C(O)=C1[C@@H]2C[C@H]2[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]2(O)C1=O OAPVUSSHCBRCOL-KBHRXELFSA-N 0.000 claims description 2
- WDLWHQDACQUCJR-ZAMMOSSLSA-N (6r,7r)-7-[[(2r)-2-azaniumyl-2-(4-hydroxyphenyl)acetyl]amino]-8-oxo-3-[(e)-prop-1-enyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)/C=C/C)C(O)=O)=CC=C(O)C=C1 WDLWHQDACQUCJR-ZAMMOSSLSA-N 0.000 claims description 2
- TVYLLZQTGLZFBW-ZBFHGGJFSA-N (R,R)-tramadol Chemical compound COC1=CC=CC([C@]2(O)[C@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-ZBFHGGJFSA-N 0.000 claims description 2
- XUBOMFCQGDBHNK-JTQLQIEISA-N (S)-gatifloxacin Chemical compound FC1=CC(C(C(C(O)=O)=CN2C3CC3)=O)=C2C(OC)=C1N1CCN[C@@H](C)C1 XUBOMFCQGDBHNK-JTQLQIEISA-N 0.000 claims description 2
- BOVGTQGAOIONJV-BETUJISGSA-N 1-[(3ar,6as)-3,3a,4,5,6,6a-hexahydro-1h-cyclopenta[c]pyrrol-2-yl]-3-(4-methylphenyl)sulfonylurea Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)NN1C[C@H]2CCC[C@H]2C1 BOVGTQGAOIONJV-BETUJISGSA-N 0.000 claims description 2
- VSNHCAURESNICA-NJFSPNSNSA-N 1-oxidanylurea Chemical compound N[14C](=O)NO VSNHCAURESNICA-NJFSPNSNSA-N 0.000 claims description 2
- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 claims description 2
- JKNCOURZONDCGV-UHFFFAOYSA-N 2-(dimethylamino)ethyl 2-methylprop-2-enoate Chemical compound CN(C)CCOC(=O)C(C)=C JKNCOURZONDCGV-UHFFFAOYSA-N 0.000 claims description 2
- CUADMYMMZWFUCY-FQEVSTJZSA-N 2-[(4-methoxyphenoxy)carbonyl-[(1s)-1-[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]ethyl]amino]acetic acid Chemical compound C1=CC(OC)=CC=C1OC(=O)N(CC(O)=O)[C@@H](C)C(C=C1)=CC=C1OCCC1=C(C)OC(C=2C=CC=CC=2)=N1 CUADMYMMZWFUCY-FQEVSTJZSA-N 0.000 claims description 2
- YFGHCGITMMYXAQ-UHFFFAOYSA-N 2-[(diphenylmethyl)sulfinyl]acetamide Chemical compound C=1C=CC=CC=1C(S(=O)CC(=O)N)C1=CC=CC=C1 YFGHCGITMMYXAQ-UHFFFAOYSA-N 0.000 claims description 2
- FSVJFNAIGNNGKK-UHFFFAOYSA-N 2-[cyclohexyl(oxo)methyl]-3,6,7,11b-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4-one Chemical compound C1C(C2=CC=CC=C2CC2)N2C(=O)CN1C(=O)C1CCCCC1 FSVJFNAIGNNGKK-UHFFFAOYSA-N 0.000 claims description 2
- GNXFOGHNGIVQEH-UHFFFAOYSA-N 2-hydroxy-3-(2-methoxyphenoxy)propyl carbamate Chemical compound COC1=CC=CC=C1OCC(O)COC(N)=O GNXFOGHNGIVQEH-UHFFFAOYSA-N 0.000 claims description 2
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 claims description 2
- WIGIZIANZCJQQY-UHFFFAOYSA-N 4-ethyl-3-methyl-N-[2-[4-[[[(4-methylcyclohexyl)amino]-oxomethyl]sulfamoyl]phenyl]ethyl]-5-oxo-2H-pyrrole-1-carboxamide Chemical compound O=C1C(CC)=C(C)CN1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCC(C)CC2)C=C1 WIGIZIANZCJQQY-UHFFFAOYSA-N 0.000 claims description 2
- MVDXXGIBARMXSA-PYUWXLGESA-N 5-[[(2r)-2-benzyl-3,4-dihydro-2h-chromen-6-yl]methyl]-1,3-thiazolidine-2,4-dione Chemical compound S1C(=O)NC(=O)C1CC1=CC=C(O[C@@H](CC=2C=CC=CC=2)CC2)C2=C1 MVDXXGIBARMXSA-PYUWXLGESA-N 0.000 claims description 2
- GSDSWSVVBLHKDQ-UHFFFAOYSA-N 9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid Chemical compound FC1=CC(C(C(C(O)=O)=C2)=O)=C3N2C(C)COC3=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-UHFFFAOYSA-N 0.000 claims description 2
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- JBMKAUGHUNFTOL-UHFFFAOYSA-N Aldoclor Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NC=NS2(=O)=O JBMKAUGHUNFTOL-UHFFFAOYSA-N 0.000 claims description 2
- ITPDYQOUSLNIHG-UHFFFAOYSA-N Amiodarone hydrochloride Chemical compound [Cl-].CCCCC=1OC2=CC=CC=C2C=1C(=O)C1=CC(I)=C(OCC[NH+](CC)CC)C(I)=C1 ITPDYQOUSLNIHG-UHFFFAOYSA-N 0.000 claims description 2
- UIERETOOQGIECD-UHFFFAOYSA-N Angelic acid Natural products CC=C(C)C(O)=O UIERETOOQGIECD-UHFFFAOYSA-N 0.000 claims description 2
- 241000416162 Astragalus gummifer Species 0.000 claims description 2
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 claims description 2
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 claims description 2
- 239000005528 B01AC05 - Ticlopidine Substances 0.000 claims description 2
- BMTAFVWTTFSTOG-UHFFFAOYSA-N Butylate Chemical compound CCSC(=O)N(CC(C)C)CC(C)C BMTAFVWTTFSTOG-UHFFFAOYSA-N 0.000 claims description 2
- 239000002083 C09CA01 - Losartan Substances 0.000 claims description 2
- 239000002080 C09CA02 - Eprosartan Substances 0.000 claims description 2
- 239000004072 C09CA03 - Valsartan Substances 0.000 claims description 2
- 239000002947 C09CA04 - Irbesartan Substances 0.000 claims description 2
- QAGYKUNXZHXKMR-UHFFFAOYSA-N CPD000469186 Natural products CC1=C(O)C=CC=C1C(=O)NC(C(O)CN1C(CC2CCCCC2C1)C(=O)NC(C)(C)C)CSC1=CC=CC=C1 QAGYKUNXZHXKMR-UHFFFAOYSA-N 0.000 claims description 2
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- A61K9/5005—Wall or coating material
- A61K9/5015—Organic compounds, e.g. fats, sugars
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- 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
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- 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
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- 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
- A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
- B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
- B65D51/00—Closures not otherwise provided for
- B65D51/24—Closures not otherwise provided for combined or co-operating with auxiliary devices for non-closing purposes
- B65D51/28—Closures not otherwise provided for combined or co-operating with auxiliary devices for non-closing purposes with auxiliary containers for additional articles or materials
- B65D51/2807—Closures not otherwise provided for combined or co-operating with auxiliary devices for non-closing purposes with auxiliary containers for additional articles or materials the closure presenting means for placing the additional articles or materials in contact with the main contents by acting on a part of the closure without removing the closure, e.g. by pushing down, pulling up, rotating or turning a part of the closure, or upon initial opening of the container
- B65D51/2814—Closures not otherwise provided for combined or co-operating with auxiliary devices for non-closing purposes with auxiliary containers for additional articles or materials the closure presenting means for placing the additional articles or materials in contact with the main contents by acting on a part of the closure without removing the closure, e.g. by pushing down, pulling up, rotating or turning a part of the closure, or upon initial opening of the container the additional article or materials being released by piercing, cutting or tearing an element enclosing it
- B65D51/2828—Closures not otherwise provided for combined or co-operating with auxiliary devices for non-closing purposes with auxiliary containers for additional articles or materials the closure presenting means for placing the additional articles or materials in contact with the main contents by acting on a part of the closure without removing the closure, e.g. by pushing down, pulling up, rotating or turning a part of the closure, or upon initial opening of the container the additional article or materials being released by piercing, cutting or tearing an element enclosing it said element being a film or a foil
- B65D51/2835—Closures not otherwise provided for combined or co-operating with auxiliary devices for non-closing purposes with auxiliary containers for additional articles or materials the closure presenting means for placing the additional articles or materials in contact with the main contents by acting on a part of the closure without removing the closure, e.g. by pushing down, pulling up, rotating or turning a part of the closure, or upon initial opening of the container the additional article or materials being released by piercing, cutting or tearing an element enclosing it said element being a film or a foil ruptured by a sharp element, e.g. a cutter or a piercer
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
- B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
- B65D81/00—Containers, packaging elements, or packages, for contents presenting particular transport or storage problems, or adapted to be used for non-packaging purposes after removal of contents
- B65D81/32—Containers, packaging elements, or packages, for contents presenting particular transport or storage problems, or adapted to be used for non-packaging purposes after removal of contents for packaging two or more different materials which must be maintained separate prior to use in admixture
- B65D81/3205—Separate rigid or semi-rigid containers joined to each other at their external surfaces
- B65D81/3211—Separate rigid or semi-rigid containers joined to each other at their external surfaces coaxially and provided with means facilitating admixture
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- 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
- A61K9/5089—Processes
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
- B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
- B65D2401/00—Tamper-indicating means
- B65D2401/15—Tearable part of the closure
- B65D2401/25—Non-metallic tear-off strips
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
- B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
- B65D2401/00—Tamper-indicating means
- B65D2401/50—Tamper-band co-operating with intermediate ring connected to the container
Definitions
- the present invention relates to a dual-chamber pack comprising a first chamber prefilled with a suspension base and a second chamber prefilled with a powder for suspension comprising an active ingredient, wherein upon activation of the dual-chamber pack, the contents of both the chambers are mixed to form an extended release suspension composition which is characterized by having no substantial change in the in-vitro dissolution release profile of the active ingredient upon storage for at least seven days.
- Extended release solid compositions are preferred dosage forms over immediate release solid compositions, especially for active ingredients showing fluctuations in the plasma concentration and for active ingredients having short half-lives.
- Extended release solid compositions can be in the form of tablets or capsules, wherein the release of the active ingredient is controlled by using a reservoir or a matrix system.
- extended release solid compositions suffer from certain drawbacks such as difficulty in swallowing, particularly for certain groups of patients, e.g., pediatrics and geriatrics, resulting in poor patient compliance.
- high doses of active ingredients lead to large-sized compositions which aggravates this problem.
- extended release liquid compositions provide the best alternative over extended release solid compositions. Extended release liquid compositions are easy to administer, thereby leading to enhanced patient compliance. Additionally, extended release liquid compositions provide a unique advantage of having a flexible dosing regimen.
- Extended release liquid compositions are conventionally administered as powder for suspensions which are to be reconstituted by the end users at the time of administration using household pre-boiled and cooled water.
- the diluent or purified water is supplied separately along with the bottle having the extended release powder for suspension.
- These conventional packs lack patient compliance and may lead to contamination due to improper quality of water. Further, there remains a possibility of dosing errors if the diluent or water is not added to the marked level.
- U.S. Patent No. 3,156,369; U.S. Patent No. 3,603,469; U.S. Patent No. 3,840,136; and U.S. Patent No. 4,982,875 disclose the use of dual-chamber packs for separately storing two compositions in two compartments which can be admixed at the time of use.
- the two compartments are separated by a breakable membrane which is ruptured by the depression of a plunger so that the one composition gets released into another and is mixed.
- the membrane fragments may get detached and fall into the final product. This may lead to undesirable contamination and can pose serious health hazards.
- the dual-chamber packs disclosed in the prior art have a limited capacity for the compartments which may not be suitable for high- dose drugs or for drugs which require chronic administration.
- the liquid composition may get permeated into the solid composition across the membrane during storage which can lead to the agglomeration of the solid composition. This may result in poor flow of the solid composition, thus affecting the content uniformity of the final product.
- the liquid composition on permeation can affect the stability of moisture-sensitive active ingredients.
- the present invention provides a patient compliant dual -chamber pack with a significant improvement over the prior art and which fulfills the unmet need of incorporating variety of active ingredients.
- the present dual -chamber pack can be suitable for any class of active ingredients including the high-dose active ingredients, active ingredients requiring chronic administration, and/or moisture-sensitive active ingredients.
- the plunger used in the pack of the instant invention is designed in a way such that the breakable membrane remains adhered to the plug at the time of activation and membrane fragments do not fall into the final product.
- the pack ensures that the final product remains safe for the use of patients.
- the pack also ensures that the solid composition is completely released into the liquid composition thereby maintaining the content uniformity of the final product. Further, the pack also ensures that there is no permeation of moisture into the chamber having solid composition comprising the active ingredient, and the stability of the active ingredient remains unaffected during storage.
- the present invention offers the reconstituted suspension compositions which provide the desired extended release of the active ingredient throughout the shelf life of the compositions.
- the suspension base prevents the leaching of the active ingredient from the coated cores and thus ensures substantially similar in-vitro dissolution release profile of the active ingredient throughout the shelf life of the compositions. This consistent in-vitro release then ensures a steady plasma concentration with no fluctuations throughout the shelf life of the compositions.
- the present invention thus provides a novel patient-compliant dual-chamber pack prefilled with solid and liquid compositions in two chambers, which upon mixing forms a unique composition providing the desired extended release of the active ingredient throughout the shelf life of the composition.
- the compositions prefilled in the dual- chamber pack remain stable during the storage.
- the present invention relates to a dual-chamber pack comprising a first chamber prefilled with a suspension base and a second chamber prefilled with a powder for suspension comprising an active ingredient, wherein upon activation of the dual-chamber pack, the contents of both the chambers are mixed to form an extended release suspension composition which is characterized by having no substantial change in the in-vitro dissolution release profile of the active ingredient upon storage for at least seven days.
- the pack allows the end-users ease of dispensing with only a few simple steps required for reconstitution.
- the pack is suitable from low to high dose active ingredients, active ingredients required for chronic administration as well as moisture-sensitive active ingredients.
- the pack ensures that the powder for suspension falls completely into the suspension base thereby maintaining the content uniformity.
- the pack also ensures that final product remains free of any contamination from the pack components and is safe to the end-users. Further, the pack ensures the stability of the active ingredient during storage.
- Figure 1 Schematic diagram of the components of a dual-chamber pack with a powder for suspension prefilled in the plunger
- Figure 2 Schematic diagram of the components of a dual-chamber pack with a powder for suspension prefilled in the reservoir
- Figure 3 Schematic diagram for the biphasic connector - top view and front view
- Figure 4 Schematic diagram representing the assembly of a dual -chamber pack with a powder for suspension prefilled in the reservoir
- Figure 5 Schematic diagram representing the functioning of a dual-chamber pack with a powder for suspension prefilled in the reservoir
- a first aspect of the invention provides a dual-chamber pack comprising;
- the powder for suspension prefilled in the second chamber is present in a volume ranging from about 0.5 cc to about 500 cc.
- the first chamber comprises of a container and the second chamber comprises of an overcap, a plunger, and a plug with a breakable polymeric membrane.
- the plunger is prefilled with the powder for suspension in a volume ranging from about 0.5 cc to about 30 cc.
- the first chamber comprises of a container and the second chamber comprises of a reservoir, a biphasic connector, a plunger, and a plug with a breakable polymeric membrane.
- the reservoir is prefilled with the powder for suspension in a volume greater than about 30 cc.
- the reservoir is prefilled with the powder for suspension in a volume ranging from about 30 cc to about 500 cc.
- the biphasic connector of the second chamber connects the reservoir to the container of the first chamber.
- the plunger ensures the breakable polymeric membrane remains attached to the plug during activation.
- the plunger comprise of one or more sharp projections with an essential continuous blunt area.
- the plunger comprise of one sharp projection with an essential continuous blunt area.
- the plunger can further have one or more grooves.
- the body of the plunger can be in the form of a cylinder or a funnel.
- the plug is made up of a polymeric material selected from the group comprising polyolefin, polyethylene, polypropylene, polyvinyl chloride, cyclic olefin polymer, cyclic olefin co-polymer, polyethylene terephthalate, polyethylene terephthalate - G, polypropylene, and polycarbonate.
- the plug is made up of polyethylene.
- the plug additionally includes one or more moisture barrier additives.
- the moisture barrier additives are selected from the plastic additive group comprising of monomers and co- polymers that get activated through polymerization process to form an effective organic chemical.
- the moisture barrier additives improve the moisture barrier properties by up to 50%.
- the moisture barrier additives improve the moisture barrier properties by up to 30%.
- the plug with the breakable polymeric membrane prevents moisture permeation from the first chamber into the second chamber.
- the extended release suspension composition is a stable composition.
- a second aspect of the present invention provides a dual-chamber pack comprising:
- a second chamber comprising:
- the overcap (1) has a means to exert pressure onto the plunger (3) so as to partially rupture the breakable polymeric membrane (5) of the plug and deliver the powder for suspension into the suspension base of the container (7); and wherein the powder for suspension is mixed with the suspension base to form an extended release suspension composition which is characterized by having no substantial change in the in-vitro dissolution release profile of the active ingredient upon storage for at least seven days.
- the plunger is prefilled with the powder for suspension in a volume ranging from about 0.5 cc to about 30 cc.
- the plunger may be opened at both the ends.
- the plunger is fitted into the overcap first, and then the powder for suspension is prefilled into the plunger which is then fitted with a plug.
- the plunger comprise of one or more sharp projections with an essential continuous blunt area.
- the plunger comprise of one sharp projection with an essential continuous blunt area.
- the overcap exerts pressure onto the plunger when it is screwed during activation of the dual -chamber pack.
- a third aspect of the present invention provides a dual -chamber pack comprising: a) a first chamber in the form of a container (8) prefilled with a suspension base provided with an opening (7) at an upper end;
- a second chamber comprising:
- a reservoir (1) adapted to fit into a plunger (2) prefilled with a powder for suspension comprising an active ingredient; the plunger (2) is further adapted to fit into a plug (3) having a top flat surface,
- the reservoir (1) at the top of the second chamber has a means to exert pressure onto the plunger (2) so as to partially rupture the breakable polymeric membrane (4) of the plug and deliver the powder for suspension into the suspension base of the container (8); the second chamber is replaced with a cap (9), and wherein the powder for suspension is mixed with the suspension base to form an extended release suspension composition which is characterized by having no substantial change in the in-vitro dissolution release profile of the active ingredient upon storage for at least seven days.
- the reservoir is prefilled with the powder for suspension in a volume greater than about 30 cc, particularly in a range from about 30 cc to about 500 cc.
- the plunger comprise of one or more sharp projections, wherein the plunger essentially has a continuous blunt area.
- the plunger comprise of one sharp projection with a continuous blunt area.
- the body of the plunger can be in the form of a cylinder or a funnel. The funnel shaped plunger further helps to increase the capacity to incorporate high dose drugs.
- the plunger is opened at both the ends.
- the cap is a conventional cap or a child-resistant cap.
- the biphasic connector has a tamper evident band on the side connected to the container of the first chamber and grooves on another side for locking with the reservoir of the second chamber.
- the reservoir exerts pressure onto the plunger when it is screwed during activation of the dual -chamber pack.
- a fourth aspect of the present invention provides a method of providing an extended release suspension composition stored in a dual-chamber pack, comprising the steps of:
- suspension comprising an active ingredient
- the plunger is prefilled with the powder for suspension in a volume ranging from about 0.5 cc to about 30 cc.
- the plunger may be open at both the ends.
- the plunger is fitted into the overcap first, and then the powder for suspension is prefilled into the plunger which is then fitted with a plug.
- the overcap may be prefitted with the plunger.
- the overcap may have a tamper-evident band which is to be removed first to start the activation process.
- a fifth aspect of the present invention provides a method of providing an extended release suspension composition stored in a dual-chamber pack, comprising the steps of:
- suspension comprising an active ingredient
- the reservoir is prefilled with the powder for suspension in a volume greater than about 30 cc, particularly in a range from about 30 cc to about 500 cc.
- the biphasic connector has a tamper evident band on the side connected to the container of the first chamber and grooves on another side for locking with the reservoir of the second chamber.
- the tamper evident band is removed first to start the activation process.
- the powder for suspension comprise of extended release coated cores of an active ingredient, optionally admixed with one or more pharmaceutically acceptable excipients.
- the powder for suspension may additionally have one or more osmogents, or one or more suspending agents.
- the core may comprise of a release-controlling agent in the form of a matrix with the active ingredient, which can be coated with a coating layer that remain insoluble in the suspension base during storage.
- the extended release coated cores comprise a core comprising an active ingredient and a coating layer over said core comprising one or more release-controlling agents.
- the core is in the form of a bead, a pellet, a granule, a spheroid, or the like.
- the active ingredient is layered onto an inert particle to form the core.
- the extended release coated cores comprise a core comprising an active ingredient in a complexed or an ion-exchange resin form and a coating layer over said core comprising one or more release-controlling agents.
- the release-controlling agent is selected from the group comprising a pH-dependent release-controlling agent, a pH- independent release-controlling agent, or mixtures thereof.
- the extended release suspension composition is characterized by having an osmolality ratio of at least about 1.
- the term "powder for suspension,” as used herein, refers to a solid composition comprising extended release coated cores of an active ingredient, optionally admixed with one or more osmogents, one or more suspending agents, or pharmaceutically acceptable excipients.
- the plunger or container of the second chamber of the present invention is prefilled with the powder for suspension.
- suspension base refers to a medium which is used to suspend the coated cores of the active ingredient.
- the suspension base of the present invention comprises one or more suspending agents, one or more osmogents, and a pharmaceutically acceptable vehicle. It may further comprise one or more
- the powder for suspension having coated cores of active ingredient may be reconstituted with the suspension base having suspending agents, osmogents, pharmaceutically acceptable excipients, and a pharmaceutically acceptable vehicle.
- the pharmaceutically acceptable excipients may be premixed with the coated cores which may be reconstituted with the pharmaceutically acceptable vehicle.
- the pharmaceutically acceptable vehicle may comprise of purified water or a mixture of purified water with one or more suitable organic solvents, in particular purified water.
- the container of the first chamber of the present invention is prefilled with a pre-formed suspension base or a pharmaceutically acceptable vehicle which forms the suspension base at the time of reconstitution.
- the suspension base generates a hypertonic condition such that there is no substantial change in the in-vitro dissolution release profile of the active ingredient upon storage of the reconstituted extended release suspension composition for at least seven days.
- the suspension base of the present invention has an osmolality of at least about 1 osmol/kg of the suspension base.
- activation means a process which reconstitutes the powder for suspension with the suspension base.
- the activation can be done by the end- users such as patients, pharmacists, or caregivers.
- the activation process starts by either screwing the overcap or the reservoir.
- extended release refers to the release profile of the active ingredient over an extended period of time, e.g. , over a period of 4, 6, 8, 12, 24 hours, or more.
- hyperertonic condition means the suspension base has higher solute concentration which helps to generate high osmotic pressure such that there is no significant leaching of active ingredient from the coated cores into the suspension base.
- the solutes are osmogents i.e., pharmaceutically acceptable inert water-soluble compounds that contribute towards generating hypertonic conditions in the suspension base.
- a saturated solution of the active ingredient present in the suspension base or the external phase may prevent the substantial leaching of the active ingredient from the extended release coated cores.
- osmolality ratio means the ratio of the osmolality of the external phase to the osmolality of the internal phase.
- the external phase herein means the suspension base without the multiple extended release coated cores of the active ingredient.
- the internal phase herein means the extended release coated cores of the active ingredient.
- the osmolality of the internal phase is represented as the osmolality of a solution which prevents significant leaching of the active ingredient from the coated cores into the solution.
- the leaching of the active ingredient from the extended release coated cores is determined by the difference in the osmolalities across the coating layer and the absence of any significant leaching from the extended release coated cores directs that the osmolality of the solution has become equal to the osmolality of the extended release coated cores.
- the osmolality ratio of the extended release suspension compositions of present invention is at least about 1.
- osmolality is expressed as number of moles of any water-soluble compound per kg of a liquid phase.
- the liquid phase can be a suspension base or a solution.
- the osmolality may be measured according to known methods, such as using a vapor pressure osmometer, a colloid osmometer, or a freezing point depression osmometer such as Osmomat 030-D or Osmomat 3000, in particular by a freezing point depression osmometer.
- inert particle refers to a particle made from a sugar sphere also known as a non-pareil seed, a microcrystalline cellulose sphere, a dibasic calcium phosphate bead, a mannitol bead, a silica bead, a tartaric acid pellet, a wax based pellet, and the like.
- substantially refers to any value which lies within the range as defined by a variation of up to ⁇ 15 from the average value.
- significant leaching means more than 20% of the active ingredient is leached out from the extended release coated cores into the solution.
- stable refers to chemical stability, wherein not more than 5% w/w of total related substances are formed on storage at 40°C and 75% relative humidity (R.H.) or at 25°C and 60% R.H. for a period of at least three months to the extent necessary for the sale and use of the composition.
- osmogent refers to all pharmaceutically acceptable inert water-soluble compounds that can imbibe water and/or aqueous biological fluids.
- the osmogent can be present in the suspension base or in the powder for suspension or both.
- Suitable examples of osmogents or pharmaceutically acceptable inert water-soluble compounds are selected from the group comprising carbohydrates such as xylitol, mannitol, sorbitol, arabinose, ribose, xylose, glucose, fructose, mannose, galactose, sucrose, maltose, lactose, dextrose and raffinose; water-soluble salts of inorganic acids such as magnesium chloride, magnesium sulfate, potassium sulfate, lithium chloride, sodium chloride, potassium chloride, lithium hydrogen phosphate, sodium hydrogen phosphate, potassium hydrogen phosphate, lithium dihydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, and sodium phosphate tribasic; water-soluble salts of organic acids such as sodium acetate, potassium acetate, magnesium succinate, sodium benzoate, sodium citrate, and sodium ascorbate; water-soluble amino acids such as glycine, leucine
- Suitable suspending agents are selected from the group comprising cellulose derivatives such as co-processed spray dried forms of microcrystalline cellulose and carboxymethyl cellulose sodium, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, methylcellulose, carboxymethyl cellulose and its salts/derivatives, and microcrystalline cellulose; carbomers; gums such as locust bean gum, xanthan gum, tragacanth gum, arabinogalactan gum, agar gum, gellan gum, guar gum, apricot gum, karaya gum, sterculia gum, acacia gum, gum arabic, and carrageenan; pectin; dextran; gelatin; polyethylene glycols; polyvinyl compounds such as polyvinyl acetate, polyvinyl alcohol, and polyvinyl pyrrolidone; sugar alcohols such as xylitol and mannitol; colloidal silica; and mixtures thereof.
- pharmaceutically acceptable excipients refers to excipients that are routinely used in pharmaceutical compositions.
- the pharmaceutically acceptable excipients may comprise glidants, sweeteners, anti-caking agents, wetting agents, preservatives, buffering agents, flavoring agents, anti-oxidants, chelating agents, and combinations thereof.
- the average diameter of the extended release coated cores ranges from about 10 um to about 2000 ⁇ , particularly from about 50 ⁇ to about 1000 um, and more particularly from about 150 ⁇ to about 500 ⁇ .
- the finer sizes of the extended release coated cores help in avoiding grittiness in the mouth and are therefore more acceptable.
- This dual -chamber pack can be used for active ingredients such as valacyclovir, metformin, azithromycin, cloxacillin, clarithromycin, erythromycin, amoxicillin alone or in combination with clavulanic acid, cefdinir, cefuroxime axetil, cefixime, cefadroxil, cefpodoxime, cefaclor, cefprozil, fluconazole, voriconazole, acarbose, miglitol, voglibose, repaglinide, nateglinide, glibenclamide, glimepride, glipizide, gliclazide, chloropropamide, tolbutamide, phenformin, alogliptin, sitagliptin, linagliptin, saxagliptin, rosiglitazone, pioglitazone, troglitazone, faraglitazar, englitazone
- hydrochloride chlorzoxazone, tolmetin, tramadol, bepridil, phenytoin, gabapentin, terbinafine, atorvastatin, doxepine, rifabutin, mesalamine, etidronate, nitrofurantoin, choline magnesium trisalicylate, theophylline, nizatidine, methocarbamol, mycophenolate mofetil, tolcapone, ticlopidine, capecitabine, orlistat, colsevelam, meperidine,
- the suspension base or the powder for suspension of the present invention may further include an immediate release component of the active ingredient to have a biphasic or pulsatile type of release.
- the immediate release component may be present in the form of a powder, a pellet, a bead, a spheroid, or a granule.
- the immediate release component may be present in the form of an immediate release coating over the extended release coated cores.
- the reconstituted extended release suspension composition of the present invention may comprise two or more different active ingredients with different type of release profiles or incompatible active ingredients.
- the release-controlling agents used to form the extended release coating are selected from a group comprising a pH-dependent release-controlling agent, a pH- independent release-controlling agent, or mixtures thereof.
- pH-dependent release-controlling agents are selected from the group comprising acrylic copolymers such as methacrylic acid and methyl methacrylate copolymers, e.g., Eudragit ® L 100 and Eudragit ® S 100, methacrylic acid and ethyl acrylate copolymers, e.g., Eudragit ® L 100-55 and Eudragit ® L 30 D-55, dimethylaminoethyl methacrylate and butyl methacrylate and methyl methacrylate copolymers e.g., Eudragit ® E 100, Eudragit ® E PO, methyl acrylate and methacrylic acid and octyl acrylate copolymers, styrene and acrylic acid copolymers, butyl acrylate and styrene and acrylic acid copolymers, and ethylacrylate-methacrylic acid copolymer; cellulose acetate phthalate;
- pH-independent release-controlling agents are selected from the group comprising cellulosic polymers such as ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethylmethyl cellulose, hydroxypropylmethyl cellulose, and carboxy methylcellulose; acrylic copolymers such as methacrylic acid copolymers, e.g., Eudragit ® RS, Eudragit ® RL, Eudragit ® NE 30 D; cellulose acetate; polyethylene derivatives e.g., polyethylene glycol and polyethylene oxide; polyvinyl alcohol; polyvinyl acetate; gums e.g., guar gum, locust bean gum, tragacanth, carrageenan, alginic acid, gum acacia, gum arabic, gellan gum, and xanthan gum; triglycerides; waxes, e.g., Compritol ® ,
- Suitable glidants are selected from the group comprising silica, calcium silicate, magnesium silicate, colloidal silicon dioxide, cornstarch, talc, stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, hydrogenated vegetable oil, and mixtures thereof.
- Suitable sweeteners are selected from the group comprising saccharine or its salts such as sodium, potassium, or calcium, cyclamate or its salt, aspartame, alitame, acesulfame or its salt, stevioside, glycyrrhizin or its derivatives, sucralose, and mixtures thereof.
- Suitable anti-caking agents are selected from the group comprising colloidal silicon dioxide, tribasic calcium phosphate, powdered cellulose, magnesium trisilicate, starch, and mixtures thereof.
- Suitable wetting agents are selected from the group comprising anionic, cationic, nonionic, or zwitterionic surfactants, or combinations thereof.
- Suitable examples of wetting agents are sodium lauryl sulphate; cetrimide; polyethylene glycols;
- polyoxyethylene-polyoxypropylene block copolymers such as poloxamers; polyglycerin fatty acid esters such as decaglyceryl monolaurate and decaglyceryl monomyristate; sorbitan fatty acid esters such as sorbitan monostearate; polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene sorbitan monooleate; polyethylene glycol fatty acid esters such as polyoxyethylene monostearate; polyoxyethylene alkyl ethers such as polyoxyethylene lauryl ether; polyoxyethylene castor oil; and mixtures thereof.
- Suitable preservatives are selected from the group comprising parabens such as methyl paraben and propyl paraben; sodium benzoate; and mixtures thereof.
- Suitable buffering agents are selected from the group comprising citric acid, sodium citrate, sodium phosphate, potassium citrate, acetate buffer, and mixtures thereof.
- Suitable flavoring agents are selected from the group consisting of peppermint, grapefruit, orange, lime, lemon, mandarin, pineapple, strawberry, raspberry, mango, passion fruit, kiwi, apple, pear, peach, apricot, cherry, grape, banana, cranberry, blueberry, black currant, red currant, gooseberry, lingon berries, cumin, thyme, basil, camille, valerian, fennel, parsley, chamomile, tarragon, lavender, dill, bargamot, salvia, aloe vera balsam, spearmint, eucalyptus, and combinations thereof.
- Suitable anti-oxidants are selected from the group comprising butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), sodium metabisulfite, ascorbic acid, propyl gallate, thiourea, tocopherols, beta-carotene, and mixtures thereof.
- BHT butylated hydroxytoluene
- BHA butylated hydroxyanisole
- sodium metabisulfite sodium metabisulfite
- ascorbic acid propyl gallate
- thiourea thiourea
- tocopherols beta-carotene, and mixtures thereof.
- Suitable chelating agents are selected from the group comprising ethylenediamine tetraacetic acid or derivatives/salts thereof, e.g., disodium edetate; dihydroxyethyl glycine; glucamine; acids, e.g., citric acid, tartaric acid, gluconic acid, and phosphoric acid; and mixtures thereof.
- ion-exchange resins such as cation- and anion-exchange matrices are well- known in the art.
- Few exemplary resin particles that can be used according to the invention include, but are not limited to, Dowex ® resins and others made by Dow
- the cores of the present invention comprising the active ingredient can be prepared by any method known in the art, e.g., extrusion-spheronoization, wet granulation, dry granulation, hot-melt extrusion granulation, spray drying, and spray congealing.
- the active ingredient can be layered onto an inert particle to form the core.
- the active ingredient particles can be directly coated with a release-controlling agent to form the microparticles or microcapsules.
- the microparticles or microcapsules can be prepared by a process of homogenization, solvent evaporation, coacervation phase separation, spray drying, spray congealing, polymer precipitation, or supercritical fluid extraction.
- the ion-exchange resins comprise loading a plurality of the resin particles with the active ingredient to form drug-resin cores. Methods of loading active ingredients onto the resin particles are generally known in the art.
- the first chamber includes a container which is in the form of a glass or a plastic or a metallic bottle.
- the reservoir of the second chamber can be made of a plastic, a metal or a glass; particularly the reservoir is a plastic bottle.
- the reservoir of the second chamber may additionally have a slippery coating or mold polishing. This coating or polishing will help to improve the flow characteristics of the powder for suspension composition during activation.
- the plunger may be inversely fitted into the plug which is subsequently screwed or snuggly fitted on to the opening of the container of the first chamber, in particularly it is screwed fitted.
- the overcap may be fitted screwed or snuggly into the plug, in particularly snuggly fitted.
- the plunger can be open at both the ends or closed at one end and open at the other end. In particular, it is open at both the ends. The plunger opened at both the ends may further increase the capacity as well as machine ability.
- the overcap may be prefitted with the plunger.
- the overcap may have a tamper evident band which is removed first to start the activation.
- the plunger is opened at both the ends.
- the biphasic connector comprises of cross bridges to give the strength.
- the bridges can be tapered at the edges to avoid any powder deposit.
- the reservoir can have serrations to have better grip for the end-users.
- the biphasic connector has a tamper-evident band on the side connected to the container of the first chamber which is removed first to start the activation process.
- the biphasic connector is having grooves on other side for locking with the reservoir. On this side, there would be instructions for the end-users regarding direction of the rotation such as clockwise rotation for activating the pack.
- tamper-evident band refers to a band attached co- axially to the overcap or to the biphasic connector. The band breaks easily on pulling apart. The tamper-evident band ensures the overall integrity of the product until activation.
- the plunger of the instant invention can comprise of one or more sharp projections with an essential continuous blunt area.
- the plunger comprise of one sharp projection with an essential continuous blunt area.
- the plunger can have a single continuous projection with a remaining continuous blunt area which can be called as a flute shaped plunger.
- the plunger can further have one or more grooves.
- the body of the plunger can be in the form of a cylinder or a funnel. The funnel shaped plunger provides additional capacity for storing high-dose active ingredients or active ingredients required for chronic administration.
- the plunger used in the instant invention ensures that the breakable polymeric membrane remains attached to the plug during activation.
- the plug and the plunger may be made up of a material selected from the group comprising polyolefin, polyethylene, polypropylene, polyvinyl chloride, cyclic olefin polymer, cyclic olefin co-polymer, polyethylene terephthalate, polyethylene terephthalate - G, polypropylene, and polycarbonate.
- the plug and the plunger are made up of polyethylene. More particularly, the plug and the plunger are made up of linear low density polyethylene (LLDPE).
- compositions of the first and second chambers of the container are separated by a polymeric breakable membrane of the plug.
- the plunger used in the instant invention helps to rupture the breakable polymeric membrane upon the application of pressure by a screw-based mechanism. When pressure is applied on the overcap or reservoir, the breakable polymeric membrane is ruptured by the plunger. The intact polymeric membrane remains attached to the circumference of the plug. In cases, where a bottle liner exists between the first and the second chambers, the plunger would break the bottle liner in the same manner as it ruptures the breakable polymeric membrane. The unabridged part of the bottle liner remains attached to the opening of the container. The plug with the breakable polymeric membrane prevents moisture permeation from the first chamber into the second chamber.
- the material used for making the plug may also include moisture barrier additives selected from the plastic additive group comprising of monomers and co-polymers that get activated through polymerization process to form an effective organic chemical.
- the moisture barrier additives used in the present invention may include any material that can prevent moisture permeation.
- the moisture barrier additives may be present in the form of a layer inside the plug.
- the moisture barrier additives may be present in an amount of 0.1% to 10% w/w, in particularly, 0.5% to 5% w/w based on total weight of the material used for making plug.
- the material used for making the reservoir may also include the moisture barrier additives.
- the barrier additives may be present in the form of a layer inside the reservoir.
- the moisture permeation test was carried out on dual chamber packs with moisture barrier additives and without moisture barrier additives as per USP (37) - 671 Containers Performance Testing.
- the moisture barrier additives used in the present invention improve the moisture barrier properties by up to 50%. In particular, the moisture barrier additives improves the moisture barrier properties by up to 30%.
- moisture barrier additives thus help to prevent the moisture permeation from the suspension base into the powder for suspension during storage.
- the active ingredient, particularly moisture-sensitive active ingredient present in the powder for suspension thus remains stable during storage.
- Example 1 The invention may be further illustrated by the following examples, which are for illustrative purposes only and should not be construed as limiting the scope of the invention in any way.
- Example 1
- step 4 The beads of step 2 were coated with the coating dispersion of step 3 and dried to form a powder for suspension.
- step 6 Metformin hydrochloride, xylitol, microcrystalline cellulose - sodium carboxymethyl cellulose, xanthan gum, strawberry flavor, sucralose, and colloidal silicon dioxide were mixed in the solution of step 5 to form a suspension base. 7.
- the powder for suspension of step 4 was prefilled in a plunger of a second chamber of a dual -chamber pack.
- step 6 The suspension base of step 6 was prefilled in a container of a first chamber of a dual- chamber pack.
- the extended release suspension composition prepared as per Example 1 (for a dose equivalent to 750 mg of metformin hydrochloride) was stored at room temperature for 120 days.
- the in-vitro dissolution was determined at 0, 45, 90, and 120 days using USP type II apparatus at 100 rpm, in 1000 mL of phosphate buffer with pH 6.8 at 37°C.
- the results of the release studies are represented in Table 1.
- the dual-chamber pack was kept for 1 month at accelerated conditions i.e., 40°C/75% R.H. After 1 month, the pack was activated to form an extended release liquid composition which was kept for 120 days at room temperature.
- the in-vitro dissolution was determined at 0, 45, 90, and 120 days using USP type II apparatus at 100 rpm, in 1000 mL of phosphate buffer with pH 6.8 at 37°C. The results of the release studies are represented in Table 2.
- the dual-chamber pack was kept for 3 months at accelerated conditions i.e., 40°C/75% R.H. After 3 months, the pack was activated to form an extended release liquid composition which was kept for 45 days at room temperature.
- the in-vitro dissolution was determined at 0 and 45 days using USP type II apparatus at 100 rpm, in 1000 mL of phosphate buffer with pH 6.8 at 37°C. The results of the release studies are represented in Table 3.
- the related substances for the extended release suspension composition prepared as per Example 1 were determined at 0 day and after storage at room temperature for 45 and 120 days.
- the powder for suspension and suspension base was stored in the dual- chamber pack for one month and for three months at 40°C/75% R.H. After one month or three months, the pack was activated to form extended release suspension compositions and then related substances were determined at 0 day and after storage at room temperature for 45 days and 120 days.
- Metformin hydrochloride and hydroxypropylmethyl cellulose were dissolved in purified water.
- Ethyl cellulose and dibutyl sebacate were dispersed in a mixture of acetone and purified water.
- step 2 The beads of step 2 were coated with the coating dispersion of step 3.
- Metformin hydrochloride, xylitol, microcrystalline cellulose - sodium carboxymethyl cellulose, xanthan gum, strawberry flavor, sucralose, and colloidal silicon dioxide were mixed.
- step 6 The coated beads of step 4 were mixed with the mixture of step 5 to form a powder for suspension.
- the powder for suspension may be stored in plunger or reservoir (depending upon the volume) of the second chamber and the vehicle (purified water) may be stored in the container of the first chamber.
- the two chambers after assembling may be activated to form the extended release suspension composition when required.
- the extended release suspension composition prepared as per Example 2 was stored at room temperature for 30 days.
- the in-vitro dissolution was determined at 0 and 30 days using USP type II apparatus at 100 rpm, in 1000 mL of phosphate buffer with pH 6.8 at 37°C.
- the results of the release studies are represented in Table 5.
- the metformin extended release powder prepared according to the Example 2 was reconstituted with required amount of purified water. This suspension was shaken manually for at least 20 minutes. This suspension was then filtered and diluted with purified water and the osmolality was measured using Osmomat 030-D.
- the osmolality of the suspension base was found to be 4.112 osmol/kg of the suspension base on day 0.
- the osmolality of the suspension base was found to be 4.328 osmol/kg of the suspension base on day 7. It is evident from the above data that the osmolality of the suspension base of the extended release suspension composition as per Example 2 remains equivalent for seven days.
- the metformin hydrochloride, xylitol, microcrystalline cellulose - sodium carboxymethyl cellulose, xanthan gum, strawberry flavor, sucralose, and colloidal silicon dioxide were mixed as per step 5 of Example 2. This mixture was reconstituted with required amount of purified water. This suspension was then filtered and diluted with purified water, and the osmolality was measured using Osmomat 030-D.
- the osmolality of the suspension base i.e., external phase was found to be 4.204 osmol/kg of the suspension base.
- the coated beads of step 4 were dispersed in different solutions as per Examples 2A-2F. These solutions were kept for seven days at room temperature. After seven days, each solution was analyzed by HPLC for metformin content. The results are represented in following Table 5. Table 5: Effect of Osmolality on Metformin Leaching
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Abstract
Description
Claims
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/IB2015/053209 WO2015166473A1 (en) | 2014-05-01 | 2015-05-01 | Extended release suspension compositions |
PCT/IB2015/055780 WO2016016845A1 (en) | 2014-07-30 | 2015-07-30 | Dual-chamber pack |
US15/133,826 US20160228379A1 (en) | 2014-05-01 | 2016-04-20 | Extended release suspension compositions |
PCT/IB2016/052486 WO2016178132A1 (en) | 2015-05-01 | 2016-05-02 | Dual-chamber pack for extended release suspension compositions |
Publications (2)
Publication Number | Publication Date |
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EP3288518A1 true EP3288518A1 (en) | 2018-03-07 |
EP3288518A4 EP3288518A4 (en) | 2018-12-12 |
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP16789381.7A Withdrawn EP3288518A4 (en) | 2015-05-01 | 2016-05-02 | Dual-chamber pack for extended release suspension compositions |
Country Status (3)
Country | Link |
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EP (1) | EP3288518A4 (en) |
CA (1) | CA2984725A1 (en) |
WO (1) | WO2016178132A1 (en) |
Families Citing this family (23)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011119839A1 (en) | 2010-03-24 | 2011-09-29 | Jazz Pharmaceuticals, Inc. | Controlled release dosage forms for high dose, water soluble and hygroscopic drug substances |
WO2016016845A1 (en) | 2014-07-30 | 2016-02-04 | Sun Pharmaceutical Industries Limited | Dual-chamber pack |
US20180104197A9 (en) | 2014-05-01 | 2018-04-19 | Sun Pharmaceutical Industries Limited | Extended release liquid compositions of metformin |
US10258583B2 (en) | 2014-05-01 | 2019-04-16 | Sun Pharmaceutical Industries Limited | Extended release liquid compositions of guanfacine |
US10398662B1 (en) | 2015-02-18 | 2019-09-03 | Jazz Pharma Ireland Limited | GHB formulation and method for its manufacture |
US10238803B2 (en) | 2016-05-02 | 2019-03-26 | Sun Pharmaceutical Industries Limited | Drug delivery device for pharmaceutical compositions |
UY37341A (en) | 2016-07-22 | 2017-11-30 | Flamel Ireland Ltd | FORMULATIONS OF GAMMA-MODIFIED RELEASE HYDROXIBUTIRATE WITH IMPROVED PHARMACOCINETICS |
US11602512B1 (en) | 2016-07-22 | 2023-03-14 | Flamel Ireland Limited | Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics |
US11504347B1 (en) | 2016-07-22 | 2022-11-22 | Flamel Ireland Limited | Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics |
US11602513B1 (en) | 2016-07-22 | 2023-03-14 | Flamel Ireland Limited | Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics |
US11986451B1 (en) | 2016-07-22 | 2024-05-21 | Flamel Ireland Limited | Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics |
US20180263936A1 (en) | 2017-03-17 | 2018-09-20 | Jazz Pharmaceuticals Ireland Limited | Gamma-hydroxybutyrate compositions and their use for the treatment of disorders |
GB2566983A (en) * | 2017-09-29 | 2019-04-03 | Epsilon Pharmaceuticals Ltd | Captopril liquid dosage form and delivery system |
CN107669683B (en) * | 2017-09-30 | 2020-07-03 | 杭州华东医药集团新药研究院有限公司 | Pharmaceutical composition containing sitagliptin and metformin |
US11426734B2 (en) | 2017-11-22 | 2022-08-30 | Ancestry.Com Dna, Llc | Sample collection kit including cap having selectively movable sleeve |
US11311884B2 (en) | 2017-11-22 | 2022-04-26 | Ancestry.Com Dna, Llc | Sample collection kit including cap having selectively movable sleeve |
EP3501476A1 (en) * | 2017-12-22 | 2019-06-26 | Sun Pharmaceutical Industries Limited | Drug delivery device for pharmaceutical compositions |
KR20210094513A (en) | 2018-11-19 | 2021-07-29 | 재즈 파마슈티칼즈 아일랜드 리미티드 | Alcohol-Resistant Drug Formulations |
BR112021013766A2 (en) | 2019-03-01 | 2021-09-21 | Flamel Ireland Limited | GAMMA-HYDROXYBUTYRATE COMPOSITIONS WITH IMPROVED PHARMACOKINETICS IN THE FED STATE |
EP3941628A4 (en) * | 2019-03-19 | 2022-12-14 | Ancestry.com DNA, LLC | Sample collection kit including cap having selectively movable sleeve |
TW202126301A (en) * | 2019-10-04 | 2021-07-16 | 愛爾蘭商席歐拉斯製藥有限公司 | Pediatric suspension formulation |
US11583510B1 (en) | 2022-02-07 | 2023-02-21 | Flamel Ireland Limited | Methods of administering gamma hydroxybutyrate formulations after a high-fat meal |
US11779557B1 (en) | 2022-02-07 | 2023-10-10 | Flamel Ireland Limited | Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics |
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Publication number | Priority date | Publication date | Assignee | Title |
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US5431915A (en) * | 1993-12-20 | 1995-07-11 | Harvey; Bryce M. | Frozen oral medication delivery system and method |
DE19847968A1 (en) * | 1998-10-17 | 2000-04-20 | Boehringer Ingelheim Pharma | Separate storage of an active material and a solvent comprises a closure cap and a container, with a chamber attached to the unit. |
AR031228A1 (en) * | 1999-12-20 | 2003-09-17 | Alcon Inc | A DEVICE FOR THE SUPPLY OF A PHARMACEUTICAL PREPARATION |
US20100092562A1 (en) * | 2002-11-26 | 2010-04-15 | Hollenbeck R Gary | Sustained-release drug delivery compositions and methods |
WO2005097040A1 (en) * | 2004-04-08 | 2005-10-20 | Idd-Eal Manufacturing Company Limited | Container for constituting a formulation in liquid form |
WO2008106399A2 (en) * | 2007-02-27 | 2008-09-04 | Anderson Michael R | Container cap having dispensing storage chamber |
-
2016
- 2016-05-02 CA CA2984725A patent/CA2984725A1/en not_active Abandoned
- 2016-05-02 WO PCT/IB2016/052486 patent/WO2016178132A1/en unknown
- 2016-05-02 EP EP16789381.7A patent/EP3288518A4/en not_active Withdrawn
Also Published As
Publication number | Publication date |
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EP3288518A4 (en) | 2018-12-12 |
WO2016178132A1 (en) | 2016-11-10 |
CA2984725A1 (en) | 2016-11-10 |
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