WO2024224407A1 - Multi-layer pellet formulation and process of preparation thereof - Google Patents
Multi-layer pellet formulation and process of preparation thereof Download PDFInfo
- Publication number
- WO2024224407A1 WO2024224407A1 PCT/IN2023/051118 IN2023051118W WO2024224407A1 WO 2024224407 A1 WO2024224407 A1 WO 2024224407A1 IN 2023051118 W IN2023051118 W IN 2023051118W WO 2024224407 A1 WO2024224407 A1 WO 2024224407A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- layer
- coating layer
- drug
- pellet
- domperidone
- Prior art date
Links
- 239000008188 pellet Substances 0.000 title claims abstract description 76
- 239000000203 mixture Substances 0.000 title claims abstract description 56
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 238000000034 method Methods 0.000 title claims description 20
- 230000008569 process Effects 0.000 title claims description 17
- 238000009472 formulation Methods 0.000 title abstract description 29
- 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 claims abstract description 48
- 229960001253 domperidone Drugs 0.000 claims abstract description 48
- SUBDBMMJDZJVOS-UHFFFAOYSA-N 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 claims abstract description 42
- 229960000381 omeprazole Drugs 0.000 claims abstract description 41
- 230000003111 delayed effect Effects 0.000 claims abstract description 23
- 239000002702 enteric coating Substances 0.000 claims abstract description 11
- 238000009505 enteric coating Methods 0.000 claims abstract description 11
- 239000007909 solid dosage form Substances 0.000 claims abstract description 8
- 239000010410 layer Substances 0.000 claims description 88
- 229940079593 drug Drugs 0.000 claims description 58
- 239000003814 drug Substances 0.000 claims description 58
- 239000011247 coating layer Substances 0.000 claims description 52
- 239000003795 chemical substances by application Substances 0.000 claims description 19
- 238000009498 subcoating Methods 0.000 claims description 18
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 11
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 11
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 11
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical group 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 10
- 239000002325 prokinetic agent Substances 0.000 claims description 10
- 229940126409 proton pump inhibitor Drugs 0.000 claims description 10
- 239000011248 coating agent Substances 0.000 claims description 9
- 238000000576 coating method Methods 0.000 claims description 9
- 239000000612 proton pump inhibitor Substances 0.000 claims description 9
- 238000011068 loading method Methods 0.000 claims description 6
- 229940117841 methacrylic acid copolymer Drugs 0.000 claims description 6
- 229920003145 methacrylic acid copolymer Polymers 0.000 claims description 6
- 229920000642 polymer Polymers 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 5
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical group CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 claims description 4
- 239000003086 colorant Substances 0.000 claims description 4
- 239000004815 dispersion polymer Substances 0.000 claims description 4
- 239000008185 minitablet Substances 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 239000004014 plasticizer Substances 0.000 claims description 4
- 239000001069 triethyl citrate Substances 0.000 claims description 4
- 235000013769 triethyl citrate Nutrition 0.000 claims description 4
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 claims description 4
- 230000004888 barrier function Effects 0.000 claims description 3
- 239000007903 gelatin capsule Substances 0.000 claims description 3
- 239000008187 granular material Substances 0.000 claims description 3
- 239000000395 magnesium oxide Substances 0.000 claims description 3
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 claims description 3
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical group [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 claims description 3
- 229920001688 coating polymer Polymers 0.000 claims description 2
- 230000001681 protective effect Effects 0.000 claims 1
- 239000002904 solvent Substances 0.000 claims 1
- 239000002775 capsule Substances 0.000 abstract description 19
- 239000012729 immediate-release (IR) formulation Substances 0.000 abstract description 16
- 229940000425 combination drug Drugs 0.000 abstract description 8
- 238000004519 manufacturing process Methods 0.000 abstract description 8
- 208000018522 Gastrointestinal disease Diseases 0.000 abstract description 5
- 238000005516 engineering process Methods 0.000 abstract description 3
- 208000010643 digestive system disease Diseases 0.000 abstract description 2
- 238000011049 filling Methods 0.000 abstract description 2
- 208000018685 gastrointestinal system disease Diseases 0.000 abstract description 2
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 13
- 239000006185 dispersion Substances 0.000 description 10
- 239000013543 active substance Substances 0.000 description 8
- 239000003826 tablet Substances 0.000 description 7
- 208000008469 Peptic Ulcer Diseases 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 238000012377 drug delivery Methods 0.000 description 6
- 201000006549 dyspepsia Diseases 0.000 description 6
- 208000024798 heartburn Diseases 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 201000008629 Zollinger-Ellison syndrome Diseases 0.000 description 5
- 201000000052 gastrinoma Diseases 0.000 description 5
- 210000002784 stomach Anatomy 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 239000000454 talc Substances 0.000 description 4
- 229910052623 talc Inorganic materials 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 3
- 229920002301 cellulose acetate Polymers 0.000 description 3
- 229960004770 esomeprazole Drugs 0.000 description 3
- SUBDBMMJDZJVOS-DEOSSOPVSA-N esomeprazole Chemical compound C([S@](=O)C1=NC2=CC=C(C=C2N1)OC)C1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-DEOSSOPVSA-N 0.000 description 3
- 239000007902 hard capsule Substances 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 2
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- IQPSEEYGBUAQFF-UHFFFAOYSA-N Pantoprazole Chemical compound COC1=CC=NC(CS(=O)C=2NC3=CC=C(OC(F)F)C=C3N=2)=C1OC IQPSEEYGBUAQFF-UHFFFAOYSA-N 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 239000011324 bead Substances 0.000 description 2
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 2
- DCSUBABJRXZOMT-IRLDBZIGSA-N cisapride Chemical compound C([C@@H]([C@@H](CC1)NC(=O)C=2C(=CC(N)=C(Cl)C=2)OC)OC)N1CCCOC1=CC=C(F)C=C1 DCSUBABJRXZOMT-IRLDBZIGSA-N 0.000 description 2
- 229960005132 cisapride Drugs 0.000 description 2
- DCSUBABJRXZOMT-UHFFFAOYSA-N cisapride Natural products C1CC(NC(=O)C=2C(=CC(N)=C(Cl)C=2)OC)C(OC)CN1CCCOC1=CC=C(F)C=C1 DCSUBABJRXZOMT-UHFFFAOYSA-N 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- MJIHNNLFOKEZEW-RUZDIDTESA-N dexlansoprazole Chemical compound CC1=C(OCC(F)(F)F)C=CN=C1C[S@@](=O)C1=NC2=CC=CC=C2N1 MJIHNNLFOKEZEW-RUZDIDTESA-N 0.000 description 2
- 229960003568 dexlansoprazole Drugs 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 229920000639 hydroxypropylmethylcellulose acetate succinate Polymers 0.000 description 2
- -1 isomers Chemical compound 0.000 description 2
- 229960003174 lansoprazole Drugs 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
- 210000000111 lower esophageal sphincter Anatomy 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- TTWJBBZEZQICBI-UHFFFAOYSA-N metoclopramide Chemical compound CCN(CC)CCNC(=O)C1=CC(Cl)=C(N)C=C1OC TTWJBBZEZQICBI-UHFFFAOYSA-N 0.000 description 2
- 229960004503 metoclopramide Drugs 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 229960005019 pantoprazole Drugs 0.000 description 2
- 229960004157 rabeprazole Drugs 0.000 description 2
- YREYEVIYCVEVJK-UHFFFAOYSA-N rabeprazole Chemical compound COCCCOC1=CC=NC(CS(=O)C=2NC3=CC=CC=C3N=2)=C1C YREYEVIYCVEVJK-UHFFFAOYSA-N 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- PSIREIZGKQBEEO-UHFFFAOYSA-N 2-(1h-benzimidazol-2-ylsulfinylmethyl)-n-methyl-n-(2-methylpropyl)aniline Chemical compound CC(C)CN(C)C1=CC=CC=C1CS(=O)C1=NC2=CC=CC=C2N1 PSIREIZGKQBEEO-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 108091006112 ATPases Proteins 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 102000057290 Adenosine Triphosphatases Human genes 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 229920003136 Eudragit® L polymer Polymers 0.000 description 1
- 229920003137 Eudragit® S polymer Polymers 0.000 description 1
- 102100021022 Gastrin Human genes 0.000 description 1
- 108010052343 Gastrins Proteins 0.000 description 1
- 206010017943 Gastrointestinal conditions Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229940122957 Histamine H2 receptor antagonist Drugs 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010067171 Regurgitation Diseases 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- ZNPLZHBZUSCANM-UHFFFAOYSA-N acetic acid;benzene-1,3-dicarboxylic acid Chemical compound CC(O)=O.OC(=O)C1=CC=CC(C(O)=O)=C1 ZNPLZHBZUSCANM-UHFFFAOYSA-N 0.000 description 1
- ZUAAPNNKRHMPKG-UHFFFAOYSA-N acetic acid;butanedioic acid;methanol;propane-1,2-diol Chemical compound OC.CC(O)=O.CC(O)CO.OC(=O)CCC(O)=O ZUAAPNNKRHMPKG-UHFFFAOYSA-N 0.000 description 1
- GAMPNQJDUFQVQO-UHFFFAOYSA-N acetic acid;phthalic acid Chemical compound CC(O)=O.OC(=O)C1=CC=CC=C1C(O)=O GAMPNQJDUFQVQO-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229940069428 antacid Drugs 0.000 description 1
- 239000003159 antacid agent Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000007963 capsule composition Substances 0.000 description 1
- 229960001631 carbomer Drugs 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 229940105329 carboxymethylcellulose Drugs 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- AOXOCDRNSPFDPE-UKEONUMOSA-N chembl413654 Chemical compound C([C@H](C(=O)NCC(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@H](CCSC)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](C)NC(=O)[C@@H](CCC(O)=O)NC(=O)[C@@H](CCC(O)=O)NC(=O)[C@@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]1N(CCC1)C(=O)CNC(=O)[C@@H](N)CCC(O)=O)C1=CC=C(O)C=C1 AOXOCDRNSPFDPE-UKEONUMOSA-N 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 239000007950 delayed release tablet Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 210000001198 duodenum Anatomy 0.000 description 1
- 239000002662 enteric coated tablet Substances 0.000 description 1
- 229960003276 erythromycin Drugs 0.000 description 1
- 210000003238 esophagus Anatomy 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 238000005243 fluidization Methods 0.000 description 1
- 210000004211 gastric acid Anatomy 0.000 description 1
- 230000030136 gastric emptying Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 159000000011 group IA salts Chemical class 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 239000003485 histamine H2 receptor antagonist Substances 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 229950007395 leminoprazole Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000007726 management method Methods 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 229940080133 omeprazole 20 mg Drugs 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 125000005498 phthalate group Chemical group 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229920002689 polyvinyl acetate Polymers 0.000 description 1
- 239000011118 polyvinyl acetate Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 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 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 238000005563 spheronization Methods 0.000 description 1
- 229940071117 starch glycolate Drugs 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000007939 sustained release tablet Substances 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 125000005591 trimellitate group Chemical group 0.000 description 1
Definitions
- the present invention relates to multi-layer dosage form.
- the multi-layer formulation of the present invention comprises fixed dose combination of proton pump inhibitors and prokinetic agents more particularly to a multi-layer formulation comprising Omeprazole and Domperidone in a single pellet and process of preparation thereof.
- Proton pump inhibitors are the most common over-the counter and prescribed medication which are generally used for treatment of various Gastrointestinal Diseases such as Gastroesophageal reflux disease, peptic ulcers, heartburn, acidity and Zollinger-Ellison syndrome.
- Gastroesophageal reflux disease (GERD) is a gastrointestinal condition in which stomach acid repeatedly flows back to the esophagus and causes heart burn and acid regurgitation.
- Peptic ulcers are a condition where stomach acid damages the lining of digestive tracts and form sores on the lining of oesophagus, stomach and small intestines.
- Zollinger-Ellison syndrome is a rare gastrointestinal disorder which occurs when one or more tumors are formed in pancreas or duodenum which release the hormone gastrin causing the stomach to release too much acid.
- PPIs are generally available in combination with histamine type 2-receptor antagonists (H2 blocker), Prokinetics agents and Antacids.
- H2 blocker histamine type 2-receptor antagonists
- Prokinetics agents Antacids.
- PPIs Proton pump inhibitors alone (PPIs) were found to be less effective than combination therapy. The most preferable combination with PPIs are Prokinetics agents.
- PPIs Proton pump inhibitors
- Omeprazole, Esomeprazole, Lansoprazole, Dexlansoprazole, Pantoprazole and Rabeprazole decreased the secretion of acid in stomach by inhibiting H+/K+ ATPase enzyme. Since PPIs are acid labile there are generally available in enteric coated formulation.
- Prokinetic agents or prokinetics for example Cisapride, Domperidone, Metoclopramide helps in controlling the acid reflux by strengthening the contractions of lower esophageal sphincter (LES) muscles and fasten Gastric emptying.
- LES esophageal sphincter
- Prior art WO2013/122554 Al discloses pellet formulation comprising Esomeprazole, the pellets of the invention comprises an inner core and an active agent layer coating coated over inner core, an intermediate and enteric coated layer.
- CN1723897 discloses a formulation comprising combination of omeprazole and domperidone.
- the invention focuses on enteric-coated tablet containing lOmg of omeprazole and lOmg of domperidone.
- IN265244 B discloses an oral composition comprising at least one gastric acid suppressing agent and one or more prokinetic agent, the prior art discloses preparation of two different tablets enclosed in a capsule.
- the objective of the present invention is to provide a fixed dose combination of Proton pump inhibitors (PPIs) and Prokinetic in a single composition.
- PPIs Proton pump inhibitors
- Another objective of the present invention is to provide fixed dose combination of Omeprazole and Domperidone in a single composition for effective treatment of Gastroesophageal reflux disease (GERD), peptic ulcers, acidity, heart burns and Zollinger-Ellision syndrome.
- GSD Gastroesophageal reflux disease
- Yet another objective of the present invention is to provide a fixed dose combination of Omeprazole and Domperidone in a single pellet composition wherein the single pellet composition is a multi-layer composition comprising delayed release Omperazole layer and immediate release Domperidone layer.
- the delayed release Omperazole layer is enteric coated and is pH dependent.
- Yet another objective of the present invention is to provide process of preparation of pellet formulation comprising fixed dose combination of Omeprazole and Domperidone wherein the pellets are enclosed in a capsule.
- the present invention discloses fixed dose combination of Omeprazole and Domperidone in a single solid dosage form, wherein the formulation comprises immediate release Domperidone and delayed release Omeprazole for effective management of Gastroesophageal reflux disease (GERD), heart burn, acidity, peptic ulcers and Zollinger-Ellison Syndrome.
- GSD Gastroesophageal reflux disease
- the present invention provides a multi-layer pellet formulation wherein Omeprazole and Domperidone are contained in the separated layers, such that on administration, Domperidone releases immediately and Omeprazole release in delayed manner, thus maximizing the therapeutic effect against various gastro-intestinal disorders.
- the dual release formulation of the present invention is formulated in a single pellet dosage form and provide a novel process of preparation thereof. The process of preparing multi-layer pellet formulation comprising delayed release omeprazole and immediate release Domperidone in a single pellet which is cost effective process and required less time for manufacturing as compared to marketed products.
- FIG. 1 is a diagrammatic representative of layering process on inner core (Sugar sphere).
- FIG. 2 is a comparative representative of present invention V/S marketed formulation wherein present invention is a multi-layer single pellet comprising delayed release omeprazole and immediate release Domperidone as a separate layer wherein marketed formulation comprises white tablet of Omeprazole and pellets of Domperidone.
- composition refers to delivery system in which active agents are delivered to the patients. This could be in the form of tablet, capsule, injection, liquid etc.
- pharmaceutically acceptable excipient refers to inert substances other than active ingredients which are used in the preparation of pharmaceutical products.
- excipients that are useful in preparing a pharmaceutical composition are generally safe and non-toxic.
- inert core refers to spheres/pellets which doesn't comprises any active agents; wherein the core is coated with multi-layer coating system.
- delayed release refers to drug delivery system which release the active agents in delayed on prolonged period of time and prevents the release of active agent in acidic environment.
- enteric-coated articles are delayed release dosage forms.
- immediate release refers to drug delivery system which release the active agent immediately after administration of active agents.
- the present invention provides a novel drug delivery system comprising fixed dose combination of Proton pump inhibitors(PPIs) and Prokinetic in a single composition wherein one of the active agents exhibits pH dependent drug release.
- PPIs Proton pump inhibitors
- the PPI's are selected from but not limited to Omeprazole, Esomeprazole, Lansoprazole, Rabeprazole, Pantoprazole, Dexlansoprazole and leminoprazole, including isomers, enantiomers and tautomers thereof, and alkaline salts thereof or combinations thereof.
- the prokinetic agents are selected from but not limited to metoclopramide, Domperidone, erythromycin, and cisapride or its salts or combinations thereof.
- the present invention provides a solid oral drug delivery system comprising delayed release PPIs and immediate release prokinetic agents wherein PPIs is preferably Omeprazole or its pharmaceutical acceptable salts thereof and Prokinetic agent is Domperidone or its pharmaceutical acceptable salts thereof.
- the present invention is used in the treatment of Gastroesophageal Reflux Disease (GERD), heart burn or acidity, peptic ulcers or Zollinger-Ellison syndrome.
- GSD Gastroesophageal Reflux Disease
- heart burn or acidity
- peptic ulcers or Zollinger-Ellison syndrome.
- the present invention provides a solid drug delivery system wherein the drug delivery system is a multilayer formulation comprising a gastro-resistant delayed drug release layer and an immediate drug release layer, wherein the gastro-resistant delayed drug release layer comprises of Omeprazole and the immediate drug release layer comprises of Domperidone.
- the present invention provides a multilayer composition comprising a gastro-resistant delayed drug release layer, wherein the drug is omeprazole.
- the present invention provides a multilayer composition comprising an immediate drug release layer, wherein the drug is Domperidone.
- the present invention provides a multilayer composition comprising a gastro-resistant delayed drug release layer, wherein the drug is omeprazole and an immediate release layer, wherein the drug is Domperidone.
- the multilayer composition of the present invention is present in the form of pellets, granules, beads, mini-tablets or tablets.
- the multilayer composition of the present invention is present in the form of pellets, granules, beads, mini-tablets or tablets, which are encapsulated in a capsule shell.
- the multilayer composition of the present invention is present in the form of pellets encapsulated in a capsule shell.
- the present invention provides a multi-layer pellet composition
- a gastro-resistant Omeprazole layer which is soluble at specific pH and an immediate release Domperidone layer and wherein the multilayer pellets are encapsulated in a capsule shell.
- the hard capsule of the present invention can be manufactured by a method known to those skilled in the art, or a commercially available hard capsule can be also used.
- the hard capsule shell is made of hydroxypropyl methyl cellulose or gelatin.
- the multilayer pellet composition of the present invention comprises a gastro-resistant delayed release layer, wherein the drug is omeprazole and an immediate release layer, wherein the drug is domperidone, further comprises an inert core, wherein the gastro-resistant delayed drug release layer is coated over the inert core and the immediate release layer is coated over the delayed drug release layer.
- the gastro-resistant delayed release layer of the present invention comprises of a first drug coating layer, a sub coating layer and a gastro-resistant polymer coating layer. Wherein the sub coating layer is coated over the first drug coating layer and the gastro-resistant layer is coated over the sub-coating layer.
- the immediate release layer comprises of the second drug coating layer and seal coating layer, wherein the seal coating layer is coated over the drug coating layer.
- the inert core of the present invention comprises of sugar sphere.
- the present invention provides a multilayer pellet composition
- a. an inert core b. a gastro-resistant delayed drug release layer comprising a first drug coating layer, a sub-coating layer and a gastro-resistant layer c. an immediate drug release layer comprising second drug coating layer and seal coating layer.
- the inert core of the present invention is a sugar sphere.
- the first drug coating layer of the present invention comprises dispersion of 13.33% w/w of omeprazole, 2.33% w/w of hydroxypropyl methyl cellulose and 0.49% w/w of magnesium oxide.
- the sub-coating layer of the gastro resistant delayer drug release layer of the present invention comprises of a film forming agent and a glidant.
- Gastro-resistant layer coating of the Gastro resistant delayed drug release layer present invention is pH sensitive layer which is insoluble in acidic pH and soluble in basic pH.
- the Gastro resistant layer comprises Gastro- resistant polymer, plasticizer, surfactant, anti-tacking agent, colorant, basifier, wherein Gastro-resistant polymer is selected from group consisting of hydroxypropyl methylcellulose phtalate (HMPCP), polyvinyl acetate phtalate (PVAP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), alginate, carbomer, carboxymethylcellulose, methacrylic acid copolymer (Eudragit L, Eudragit S, Acrycoat), shellac, cellulose acetate phthalate (CAP), starch glycolate, polacrylin, methyl cellulose acetate phtalate, hydroxypropyulcellulose acetate phthalate, cellulose acetate terephtahalate, cellulose acetate isophthalate and cellulose acetate trimellitate.
- HMPCP hydroxypropyl methylcellulose phtalate
- PVAP polyvinyl acetate p
- the Gastro-resistant layer is methacrylic acid copolymer present in an amount of 16.00 %w/w based on dry polymer and 53.33 % w/v based on dispersion weight.
- the enteric coated pellet is further coated with layer comprising Domperidone and further protected with a seal coat.
- the Gastro-resistant coating layer stops the release of PPIs in acidic environment thus protecting the PPIs by forming a Gastro resistant layer.
- the second drug coating layer of the present invention comprises of domeperidone, a film forming agent, plasticizer and a colorant
- domperidone is present in an amount of 6.67% w/w
- hydroxypropyl methylcellulose is present as film forming agent in an amount of 0.97%
- triethyl citrate as plasticizer present in an amount 0.33%
- colorant present in an amount 0.33% w/w based on total weight of pellet formulation.
- the seal coating layer of the immediate release layer of the present invention is comprised a film forming agent and anti-tacking agent.
- the film forming agent is hydroxypropyl methylcellulose present in an amount 0.54% w/w and anti-tacking agent is talc present in an amount of 0.37% w/w based on total weight of pellet formulation.
- the present invention provides a multi-layer pellets which is further filled into a hard gelatin capsule.
- the multi-layer pellets of the present invention are formed by forming a layer containing Omerprazole on an inert core, more particularly a sugar sphere, subjected the drug loading core to sub coating and enteric coating and the forming a layer containing Domperidone on the enteric coated layer wherein Domperidone layer is an immediate release layer.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising: i. An inert core ii. First drug coating layer iii. A sub coating iv. Enteric coating v. Second drug coating layer vi. Seal coating layer
- the present invention comprises a multi-layer composition
- a multi-layer composition comprising: i. an inert core wherein inert core is a sugar sphere and; ii. first drug coating layer comprising omeprazole iii. a sub-coating layer surrounding the first drug coating layer iv. a gastro-resistant layer comprising methacrylic acid copolymer v. second drug coating layer comprising Domperidone vi. a seal coating layer
- the present invention provides a multiplayer pellet composition
- a multiplayer pellet composition comprising: i. an inert core wherein the inert core is a sugar sphere ii. a first drug coating layer comprising omeprazole in the amount of 13.33% w/w iii. a sub-coating surrounding the drug coating layer iv. a gastro-resistant layer comprising methacrylic acid copolymer present in the amount of 16.00% v. a second drug coating layer comprising Domperidone in the amount of 6.67% w/w, vi. a seal coating layer over the Domperidone drug coating layer
- the pellets of the present invention can be prepared by different process based on three principles i.e. Layering, extrusion-Spheronization and build-up granulation.
- the present invention utilizes layering technology for preparation of pellets comprising delayed release PPIs and immediate release prokinetic agents.
- the multi-layer pellet manufacturing technology of the present invention is cost effective and required less time for manufacturing as compared to existing formulation which generally involves preparation of separate Omeprazole Enteric coating pellets & Domperidone pellets and then filling the same in capsule.
- the multi-layer pellet in accordance with the present invention provides a novel formulation and process resulting in a reduced size, average weight and fill weight as compared to marketed capsule formulation (OMEJEL-DM).
- the present invention provides a multilayer pellets wherein the weight of the capsule was reduced by about 55% in comparison to the weight of the marketed capsule.
- the subject invention has the advantage of reduction in cost and manufacturing process as well increasing the patient's convenience as some patients have difficulty in swallowing large size capsules.
- the present invention provides a process of preparation of multi-layer pellets wherein the process involves following steps: i. Drug loading of omeprazole on an inert core wherein inert core is a sugar pellet ii. Sub-coating the drug loaded pellet with polymer dispersion. iii. Enteric coating the sub coated pellet with a Gastro-resistant polymer iv. Drug loading of Domperidone on enteric coated pellet v. Barrier coating of Domperidone with a seal coating polymer dispersion
- a sub-coating dispersion solution consisting of Hydroxypropyl methylcellulose, talc dissolved in purified water were sprayed on omeprazole loaded pellets to form a sub-coating layer.
- Enteric coating [0068] Polysorbate 80, triethyl citrate were mixed in purified water, to this solution talc, titanium dioxide and Methacrylic acid copolymer were mixed into the solution to form enteric coating dispersion. This enteric coating solution was coated over sub-coated pellets to form enteric coating layer.
- Enteric coated pellets were loaded into fluid bed system were fluidized with domperidone dispersion comprising hydroxypropyl methylcellulose, triethyl citrate. The dispersion was coated over enteric coated pellets to form a layer containing Domperidone. 0 Seal coating:
- present composition is chemically non-inferior and have similar chemical characteristic as that of present marketed formulation.
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention provides a fixed dose combination of Omeprazole and Domperidone in a single solid dosage form, wherein the formulation comprises immediate release Domperidone and delayed release Omeprazole for effective management of Gastro-intestinal disorder. The present invention related to multi-layer pellet composition comprising enteric coated Omeprazole layer which releases Omeprazole at specific pH and immediate release Domperidone layer. The single multi-layer pellet manufacturing technology of the present invention is cost effective and required less manufacturing time as compared to existing formulation which generally involves preparation of separate Omeprazole Enteric coating pellets & Domperidone pellets and then filling the same in capsule.
Description
MULTI-LAYER PELLET FORMULATION AND PROCESS OF PREPARATION THEREOF
FIELD OF INVENTION:
[001] The present invention relates to multi-layer dosage form. The multi-layer formulation of the present invention comprises fixed dose combination of proton pump inhibitors and prokinetic agents more particularly to a multi-layer formulation comprising Omeprazole and Domperidone in a single pellet and process of preparation thereof.
BACKGROUND:
[002] Proton pump inhibitors are the most common over-the counter and prescribed medication which are generally used for treatment of various Gastrointestinal Diseases such as Gastroesophageal reflux disease, peptic ulcers, heartburn, acidity and Zollinger-Ellison syndrome. Gastroesophageal reflux disease (GERD) is a gastrointestinal condition in which stomach acid repeatedly flows back to the esophagus and causes heart burn and acid regurgitation. Proton pump inhibitors used to relive GERD. Peptic ulcers are a condition where stomach acid damages the lining of digestive tracts and form sores on the lining of oesophagus, stomach and small intestines. Zollinger-Ellison syndrome is a rare gastrointestinal disorder which occurs when one or more tumors are formed in pancreas or duodenum which release the hormone gastrin causing the stomach to release too much acid. PPIs are generally available in combination with histamine type 2-receptor antagonists (H2 blocker), Prokinetics agents and Antacids. Proton pump inhibitors alone (PPIs) were found to be less effective than combination therapy. The most preferable combination with PPIs are Prokinetics agents.
[003] Proton pump inhibitors (PPIs) for example Omeprazole, Esomeprazole, Lansoprazole, Dexlansoprazole, Pantoprazole and Rabeprazole decreased the
secretion of acid in stomach by inhibiting H+/K+ ATPase enzyme. Since PPIs are acid labile there are generally available in enteric coated formulation.
[004] Prokinetic agents, or prokinetics for example Cisapride, Domperidone, Metoclopramide helps in controlling the acid reflux by strengthening the contractions of lower esophageal sphincter (LES) muscles and fasten Gastric emptying.
[005] Thus, combining PPIs and prokinetic agents is a rational approach for effective treatment of gastrointestinal disorders such as acidity, heartburn, peptic ulcers, Gastroesophageal reflux disease (GERD) and Zollinger-Ellison syndrome.
[006] Prior art WO2013/122554 Al discloses pellet formulation comprising Esomeprazole, the pellets of the invention comprises an inner core and an active agent layer coating coated over inner core, an intermediate and enteric coated layer.
[007] CN1723897 discloses a formulation comprising combination of omeprazole and domperidone. The invention focuses on enteric-coated tablet containing lOmg of omeprazole and lOmg of domperidone.
[008] IN265244 B discloses an oral composition comprising at least one gastric acid suppressing agent and one or more prokinetic agent, the prior art discloses preparation of two different tablets enclosed in a capsule.
[009] Commercially available products and literatures known in the prior art are in form of either sustained release or delayed release tablets or pellets which are further filled in a capsule. The process generally involves preparation of Omeprazole Enteric coating pellets/tablets & Domperidone Tablets/pellets separately which added cost to the manufacturing and is time consuming, involved manufacturing of two different dosage form, less time consuming and cost effective.
Objective:
[0010] The objective of the present invention is to provide a fixed dose combination of Proton pump inhibitors (PPIs) and Prokinetic in a single composition.
[0011] Another objective of the present invention is to provide fixed dose combination of Omeprazole and Domperidone in a single composition for effective treatment of Gastroesophageal reflux disease (GERD), peptic ulcers, acidity, heart burns and Zollinger-Ellision syndrome.
[0012] Yet another objective of the present invention is to provide a fixed dose combination of Omeprazole and Domperidone in a single pellet composition wherein the single pellet composition is a multi-layer composition comprising delayed release Omperazole layer and immediate release Domperidone layer. The delayed release Omperazole layer is enteric coated and is pH dependent.
[0013] Yet another objective of the present invention is to provide process of preparation of pellet formulation comprising fixed dose combination of Omeprazole and Domperidone wherein the pellets are enclosed in a capsule.
SUMMARY OF THE INVENTION:
[0014] The present invention discloses fixed dose combination of Omeprazole and Domperidone in a single solid dosage form, wherein the formulation comprises immediate release Domperidone and delayed release Omeprazole for effective management of Gastroesophageal reflux disease (GERD), heart burn, acidity, peptic ulcers and Zollinger-Ellison Syndrome.
[0015] In an aspect the present invention provides a multi-layer pellet formulation wherein Omeprazole and Domperidone are contained in the separated layers, such that on administration, Domperidone releases immediately and Omeprazole release in delayed manner, thus maximizing the therapeutic effect against various gastro-intestinal disorders.
[0016] The dual release formulation of the present invention is formulated in a single pellet dosage form and provide a novel process of preparation thereof. The process of preparing multi-layer pellet formulation comprising delayed release omeprazole and immediate release Domperidone in a single pellet which is cost effective process and required less time for manufacturing as compared to marketed products.
BRIEF DESCRIPTION OF THE FIGURES:
[0017] FIG. 1 is a diagrammatic representative of layering process on inner core (Sugar sphere).
[0018] FIG. 2 is a comparative representative of present invention V/S marketed formulation wherein present invention is a multi-layer single pellet comprising delayed release omeprazole and immediate release Domperidone as a separate layer wherein marketed formulation comprises white tablet of Omeprazole and pellets of Domperidone.
DETAILED DESCRIPTION OF INVENTION:
[0019] Those skilled in the art will be aware that the present disclosure is subject to variations and modifications other than those specifically described. It is to be understood that the present disclosure includes all such variations and modifications. The disclosure also includes all such compositions, components of the composition, referred to or indicated in this specification, individually or collectively and all combinations of any or more of such components or composition.
Definitions
[0020] For convenience, before further description of the present disclosure, certain terms employed in the specification, and examples are collected here. These definitions should be read in the light of the remainder of the disclosure and understood as by a person of skill in the art. The terms used herein have
their meanings recognized and known to those of skill in the art, however, for convenience and completeness, particular terms and their meanings are set forth below.
[0021] The articles "a", "an" and "the" are used to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article.
The terms "comprise" and "comprising" are used in the inclusive, open sense, meaning that additional elements may be included. It is not intended to be construed as "consists of only".
[0022] Throughout this specification, unless the context requires otherwise the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated element or step or group of element or steps but not the exclusion of any other element or step or group of element or steps.
[0023] The term "including" is used to mean "including but not limited to". "Including" and "including but not limited to" are used interchangeably.
[0024] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the disclosure, the preferred methods, and materials are now described. All publications mentioned herein are incorporated herein by reference.
[0025] The present disclosure is not to be limited in scope by the specific embodiments described herein, which are intended for the purposes of exemplification only. Functionally equivalent products and processes are clearly within the scope of the disclosure, as described herein.
[0026] The term "pharmaceutical composition" refers to delivery system in which active agents are delivered to the patients. This could be in the form of tablet, capsule, injection, liquid etc.
[0027] The term "pharmaceutically acceptable excipient" refers to inert substances other than active ingredients which are used in the preparation of pharmaceutical products. The excipients that are useful in preparing a pharmaceutical composition are generally safe and non-toxic.
[0028] The term "inert core" as used herein refers to spheres/pellets which doesn't comprises any active agents; wherein the core is coated with multi-layer coating system.
[0029] The term "delayed release" as used herein refers to drug delivery system which release the active agents in delayed on prolonged period of time and prevents the release of active agent in acidic environment. For the purpose of this invention enteric-coated articles are delayed release dosage forms.
[0030] The term "immediate release" as used herein refers to drug delivery system which release the active agent immediately after administration of active agents.
[0031] In an embodiment the present invention provides a novel drug delivery system comprising fixed dose combination of Proton pump inhibitors(PPIs) and Prokinetic in a single composition wherein one of the active agents exhibits pH dependent drug release.
[0032] In an embodiment the PPI's are selected from but not limited to Omeprazole, Esomeprazole, Lansoprazole, Rabeprazole, Pantoprazole, Dexlansoprazole and leminoprazole, including isomers, enantiomers and tautomers thereof, and alkaline salts thereof or combinations thereof.
[0033] In an embodiment the prokinetic agents are selected from but not limited to metoclopramide, Domperidone, erythromycin, and cisapride or its salts or combinations thereof.
[0034] In an another embodiment, the present invention provides a solid oral drug delivery system comprising delayed release PPIs and immediate release prokinetic agents wherein PPIs is preferably Omeprazole or its pharmaceutical acceptable salts thereof and Prokinetic agent is Domperidone or its pharmaceutical acceptable salts thereof.
[0035] In an another embodiment the present invention is used in the treatment of Gastroesophageal Reflux Disease (GERD), heart burn or acidity, peptic ulcers or Zollinger-Ellison syndrome.
[0036] In another embodiment the present invention provides a solid drug delivery system wherein the drug delivery system is a multilayer formulation comprising a gastro-resistant delayed drug release layer and an immediate drug release layer, wherein the gastro-resistant delayed drug release layer comprises of Omeprazole and the immediate drug release layer comprises of Domperidone.
[0037] In another embodiment the present invention provides a multilayer composition comprising a gastro-resistant delayed drug release layer, wherein the drug is omeprazole.
[0038] In an another embodiment the present invention provides a multilayer composition comprising an immediate drug release layer, wherein the drug is Domperidone.
[0039] In a preferred embodiment the present invention provides a multilayer composition comprising a gastro-resistant delayed drug release layer, wherein the drug is omeprazole and an immediate release layer, wherein the drug is Domperidone.
[0040] In a preferred embodiment the multilayer composition of the present invention is present in the form of pellets, granules, beads, mini-tablets or tablets. In a preferred embodiment the multilayer composition of the present invention is present in the form of pellets, granules, beads, mini-tablets or tablets, which are encapsulated in a capsule shell. In a most preferred embodiment the multilayer composition of the present invention is present in the form of pellets encapsulated in a capsule shell.
[0041] In an another embodiment the present invention provides a multi-layer pellet composition comprising a gastro-resistant Omeprazole layer which is soluble at specific pH and an immediate release Domperidone layer and wherein the multilayer pellets are encapsulated in a capsule shell.
[0042] The hard capsule of the present invention can be manufactured by a method known to those skilled in the art, or a commercially available hard capsule can be also used. In an embodiment the hard capsule shell is made of hydroxypropyl methyl cellulose or gelatin.
[0043] In an another embodiment the multilayer pellet composition of the present invention comprises a gastro-resistant delayed release layer, wherein the drug is omeprazole and an immediate release layer, wherein the drug is domperidone, further comprises an inert core, wherein the gastro-resistant delayed drug release layer is coated over the inert core and the immediate release layer is coated over the delayed drug release layer.
[0044] In another embodiment the gastro-resistant delayed release layer of the present invention comprises of a first drug coating layer, a sub coating layer and a gastro-resistant polymer coating layer. Wherein the sub coating layer is coated over the first drug coating layer and the gastro-resistant layer is coated over the sub-coating layer.
[0045] In an embodiment the immediate release layer comprises of the second drug coating layer and seal coating layer, wherein the seal coating layer is coated over the drug coating layer.
[0046] In an embodiment the inert core of the present invention comprises of sugar sphere.
[0047] Thus in an embodiment the present invention provides a multilayer pellet composition comprising: a. an inert core, b. a gastro-resistant delayed drug release layer comprising a first drug coating layer, a sub-coating layer and a gastro-resistant layer c. an immediate drug release layer comprising second drug coating layer and seal coating layer. wherein the inert core of the present invention is a sugar sphere.
[0048] In an embodiment the first drug coating layer of the present invention comprises dispersion of 13.33% w/w of omeprazole, 2.33% w/w of hydroxypropyl methyl cellulose and 0.49% w/w of magnesium oxide.
[0049] In an embodiment the sub-coating layer of the gastro resistant delayer drug release layer of the present invention comprises of a film forming agent and a glidant.
[0050] In an embodiment Gastro-resistant layer coating of the Gastro resistant delayed drug release layer present invention is pH sensitive layer which is insoluble in acidic pH and soluble in basic pH.
[0051] In an another embodiment the Gastro resistant layer comprises Gastro- resistant polymer, plasticizer, surfactant, anti-tacking agent, colorant, basifier, wherein Gastro-resistant polymer is selected from group consisting of hydroxypropyl methylcellulose phtalate (HMPCP), polyvinyl acetate phtalate (PVAP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), alginate,
carbomer, carboxymethylcellulose, methacrylic acid copolymer (Eudragit L, Eudragit S, Acrycoat), shellac, cellulose acetate phthalate (CAP), starch glycolate, polacrylin, methyl cellulose acetate phtalate, hydroxypropyulcellulose acetate phthalate, cellulose acetate terephtahalate, cellulose acetate isophthalate and cellulose acetate trimellitate.
[0052] In a preferred embodiment the Gastro-resistant layer is methacrylic acid copolymer present in an amount of 16.00 %w/w based on dry polymer and 53.33 % w/v based on dispersion weight. The enteric coated pellet is further coated with layer comprising Domperidone and further protected with a seal coat.
[0053] In an another embodiment the Gastro-resistant coating layer stops the release of PPIs in acidic environment thus protecting the PPIs by forming a Gastro resistant layer.
[0054] In an embodiment the second drug coating layer of the present invention comprises of domeperidone, a film forming agent, plasticizer and a colorant, In a preferred embodiment, domperidone is present in an amount of 6.67% w/w, hydroxypropyl methylcellulose is present as film forming agent in an amount of 0.97%. triethyl citrate as plasticizer present in an amount 0.33% and colorant present in an amount 0.33% w/w based on total weight of pellet formulation.
[0055] In an embodiment the seal coating layer of the immediate release layer of the present invention is comprised a film forming agent and anti-tacking agent.
[0056] In a further embodiment the film forming agent is hydroxypropyl methylcellulose present in an amount 0.54% w/w and anti-tacking agent is talc present in an amount of 0.37% w/w based on total weight of pellet formulation.
[0057] In an embodiment, the present invention provides a multi-layer pellets which is further filled into a hard gelatin capsule. The multi-layer pellets of the present invention are formed by forming a layer containing Omerprazole on an inert core, more particularly a sugar sphere, subjected the drug loading core to
sub coating and enteric coating and the forming a layer containing Domperidone on the enteric coated layer wherein Domperidone layer is an immediate release layer.
[0058] In an embodiment the present invention provides a pharmaceutical composition comprising: i. An inert core ii. First drug coating layer iii. A sub coating iv. Enteric coating v. Second drug coating layer vi. Seal coating layer
[0059] In an embodiment the present invention comprises a multi-layer composition comprising: i. an inert core wherein inert core is a sugar sphere and; ii. first drug coating layer comprising omeprazole iii. a sub-coating layer surrounding the first drug coating layer iv. a gastro-resistant layer comprising methacrylic acid copolymer v. second drug coating layer comprising Domperidone vi. a seal coating layer
[0060] In an embodiment the present invention provides a multiplayer pellet composition comprising: i. an inert core wherein the inert core is a sugar sphere ii. a first drug coating layer comprising omeprazole in the amount of 13.33% w/w iii. a sub-coating surrounding the drug coating layer iv. a gastro-resistant layer comprising methacrylic acid copolymer present in the amount of 16.00%
v. a second drug coating layer comprising Domperidone in the amount of 6.67% w/w, vi. a seal coating layer over the Domperidone drug coating layer
[0061] The pellets of the present invention can be prepared by different process based on three principles i.e. Layering, extrusion-Spheronization and build-up granulation. In an embodiment the present invention utilizes layering technology for preparation of pellets comprising delayed release PPIs and immediate release prokinetic agents.
[0062] The multi-layer pellet manufacturing technology of the present invention is cost effective and required less time for manufacturing as compared to existing formulation which generally involves preparation of separate Omeprazole Enteric coating pellets & Domperidone pellets and then filling the same in capsule.
[0063] Preferably, the multi-layer pellet in accordance with the present invention, provides a novel formulation and process resulting in a reduced size, average weight and fill weight as compared to marketed capsule formulation (OMEJEL-DM). In an embodiment the present invention provides a multilayer pellets wherein the weight of the capsule was reduced by about 55% in comparison to the weight of the marketed capsule. Thus the subject invention has the advantage of reduction in cost and manufacturing process as well increasing the patient's convenience as some patients have difficulty in swallowing large size capsules.
[0064] In an another embodiment, the present invention provides a process of preparation of multi-layer pellets wherein the process involves following steps: i. Drug loading of omeprazole on an inert core wherein inert core is a sugar pellet ii. Sub-coating the drug loaded pellet with polymer dispersion. iii. Enteric coating the sub coated pellet with a Gastro-resistant polymer
iv. Drug loading of Domperidone on enteric coated pellet v. Barrier coating of Domperidone with a seal coating polymer dispersion
[0065] The present invention will hereinafter be described in further details by examples. It is to be understood that these examples are presented for illustrative purpose only and not intended to limit the scope of the present invention.
Example-1
Table 1-Formula for Omeprazole EC 13.33% w/w + Domperidone IR 6.67% w/w
(Single pellet)
Example-2:
Process of Preparation Omeprazole EC 13.33% w/w + Domperidone IR 6.67% w/w (Single pellet) Coating of inert core with Omeprazole:
[0066] Inert sugar pellets were placed in a fluid bed system for fluidization of pellets. A dispersion solution of 13.33% w/w Omeprazole, 2.33% hydroxypropyl Methylcellulose, 0.49% magnesium oxide in water were sprayed on sugar pellets to for a layer. Sub coating:
[0067] After loading the sugar pellets with Omeprazole dispersion, a sub-coating dispersion solution consisting of Hydroxypropyl methylcellulose, talc dissolved in purified water were sprayed on omeprazole loaded pellets to form a sub-coating layer. Enteric coating:
[0068] Polysorbate 80, triethyl citrate were mixed in purified water, to this solution talc, titanium dioxide and Methacrylic acid copolymer were mixed into the solution to form enteric coating dispersion. This enteric coating solution was coated over sub-coated pellets to form enteric coating layer.
5 Domperidone coating:
[0069] Enteric coated pellets were loaded into fluid bed system were fluidized with domperidone dispersion comprising hydroxypropyl methylcellulose, triethyl citrate. The dispersion was coated over enteric coated pellets to form a layer containing Domperidone. 0 Seal coating:
[0070] Hydroxypropyl methylcellulose and talc were dissolved in purified water to form dispersion solution; the dispersion was coated over Domperidone coated layer to form a film or barrier layer.
Example-3: 5 COMPARATIVE STUDIES
[0071] The multi-layer formulation of present study as per example-1 was compared with marketed formulation of OMEJEL-DM, which is hardgel capsule comprising Omeprazole 20mg mini-tablet & Domperidone lOmg pellets. The formulations were subjected for different experimental study whose results are 0 mentioned in below tables:
3.a: Table-2 Comparative product Characterization
[0072] From table 2, it was clearly observed that multi-layer single pellet composition has reduced capsule size, average weight and fill weight as compared to market capsule therefore the present invention is a cost effective process.
5 3.b. Table-3: Comparative chemical evaluation of market Product Omejel-Dm vs multi-layer pellet of present invention
[0073] As per table-3 it was observed that present composition is chemically non-inferior and have similar chemical characteristic as that of present marketed formulation.
5 3.c.: Table-4 Stability data of formulation as per Example 1
3.d. Table 5- Stability data of Omejel-DM
[0074] Conclusion - From Table 2 it can be observed that the fill weight of the capsule prepared from the pellets based on the present invention was more then 60-70% less than the marketed formulation. Thus the multi-layer single pellet composition has reduced capsule size, average weight and fills weight as compared to market capsule therefore the present invention is cost-effective
[0075] Although the weight of the capsule was 60 to 70% lesser compared to the marketed conventional formulation, from table 3 to 5 it can be observed that the stability and dissolution and disintegration profiles were non-inferior or better than the marketed formulation.
Claims
1. A multi-layer solid dosage form comprising: a. an inert core and; b. a first drug coating layer comprising an effective amount of proton pump inhibitors surrounding the inert core and; c. a sub-coating layer surrounding the drug coating layer and; d. a gastro-resistant layer surrounding the inert core and; e. a second drug coating layer comprising an effective amount of Prokinetic agents. f. a seal coating layer,
2. A multi-layer solid dosage form as claimed in claim 1 wherein the inert core is a sugar sphere.
3. A multi-layer solid dosage form as claimed in claim 1 wherein the first drug coating layer comprises omeprazole or a pharmaceutically acceptable salts thereof as proton pump inhibitors
4. A multi-layer solid dosage form as claimed in claim 1 wherein the second drug coating layer comprises Domperidone or a pharmaceutically acceptable salts thereof as Prokinetic agent.
5. A multi-layer solid dosage form as claimed in claim 1 is in form of pellet or granules, or minitablets form wherein multi-layer solid dosage form is a pellet.
6. A multi-layer pellet composition as claimed in any of claims 1-5 comprising: a) an inert sugar core and; b) a drug coating layer comprising omeprazole present in an amount 13.33% w/v and; c) a sub-coating layer surrounding the drug coating layer and; d) a gastro-resistant layer comprising methacrylic acid copolymer present in amount 16.00 % w/w surrounding the sub-coating layer and; e) a second drug coating layer comprising Domperidone present in amount 6.67% w/w surrounding the gastro-resistant layer and; f) a seal coating layer
7. A multilayer pellet as claimed in claim 1 and 6 comprises: a) the inert core, b) the first drug coating layer, c) the sub-coating layer and d) the gastro resistant layer forms the gastro resistant delayed drug release layer and e) the second drug coating layer and f) the seal coating layer forms the immediate drug release layer
8. A multi-layer pellet as claimed in claim 6 wherein drug coating layer further comprises excipients selected from film forming agent, basicity agent and a coating solvent wherein film forming agent is hydroxypropyl methylcellulose and basicity agent is magnesium oxide.
9. A multi-layer pellet as claimed in claim 6, wherein immediate layer further comprises excipients selected from film forming agent, plastricizer and a colorant, this layer is further coated with a protective seal coating layer comprising film forming agent and antitacking agent wherein film forming agent is hydroxypropyl methylcellulose and plasticizer is triethyl citrate.
10. A multi-layer pellet as claimed in claim 6 are further enclosed in a hard gelatin capsule.
11. A process of preparation of multi-layer pellet composition comprising: i. Drug loading of omeprazole on an inert core wherein inert core is a sugar pellet and; ii. Sub-coating the drug loaded pellet with polymer dispersion and; iii. Enteric coating the sub coated pellet with a Gastro-resistant polymer and; iv. Drug loading of Domperidone on enteric coated pellet and; v. Barrier coating of Domperidone with a seal coating polymer dispersion
Wherein the pellets are further filled in a hard gelatin capsule.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN202311030819 | 2023-04-28 | ||
| IN202311030819 | 2023-04-28 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2024224407A1 true WO2024224407A1 (en) | 2024-10-31 |
Family
ID=93255962
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IN2023/051118 WO2024224407A1 (en) | 2023-04-28 | 2023-11-30 | Multi-layer pellet formulation and process of preparation thereof |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2024224407A1 (en) |
-
2023
- 2023-11-30 WO PCT/IN2023/051118 patent/WO2024224407A1/en unknown
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US9636306B2 (en) | Proton pump-inhibitor-containing capsules which comprise subunits differently structured for a delayed release of the active ingredient | |
| US20100178334A1 (en) | Oral Pharmaceutical Dosage Form Comprising as Active Ingredients a Proton Pump Inhibitor together with Acetyl Salicyclic Acid | |
| US20060165797A1 (en) | Dosage form for treating gastrointestinal disorders | |
| US20070231388A1 (en) | Novel Pharmaceutical Dosage Form and Manufacturing Process | |
| BG65008B1 (en) | Oral pharmaceutical pulsed release dosage | |
| WO2006011159A2 (en) | Stabilized pharmaceutical composition containing rabeprazole sodium with improved bioavailability | |
| KR20070083956A (en) | New modified release tablet formulations for proton pump inhibitors | |
| US20080095853A1 (en) | Modified Release For Proton Pump Inhibitors | |
| JP2003504338A (en) | Heartburn treatment | |
| US20240033224A1 (en) | Enteric-coated pellet, method for preparing same and formulation comprising same | |
| WO2024224407A1 (en) | Multi-layer pellet formulation and process of preparation thereof | |
| WO2009137648A1 (en) | Multilayer proton pump inhibitor tablets | |
| AU2007311493B2 (en) | Multiple unit tablet compositions of benzimidazole compounds | |
| WO2004066982A1 (en) | Stable oral benzimidazole compositions and processes for their preparation | |
| US20120321702A1 (en) | Pharmaceutical composition of lansoprazole | |
| EP1841409A2 (en) | Dosage form for treating gastrointestinal disorders | |
| EP3292862A1 (en) | Omeprazole formulations | |
| WO2010018593A2 (en) | Gastric acid resistant benzimidazole multiple unit tablet composition | |
| KR20240014209A (en) | Tablet Comprising Dexlansoprazole | |
| WO2009113090A2 (en) | Process for preparing an oral formulation of an acid-sensitive benzimidazole drug |