Immediate-release formulations of acid-labile pharmaceutical compositions
The present invention provides, inter alia, compositions comprising a pH buffering agent and a controlled-release component containing an acid-labile pharmaceutical agent. Methods of using such compositions are also provided.
1 . A solid pharmaceutical composition, comprising:
(a) a gastrointestinal-disorder-effective amount of at least one enteric-coated proton pump inhibitor which proton pump inhibitor is acid labile; and
(b) at least one buffering agent; wherein upon oral administration, the enteric coating substantially dissolves in gastrointestinal fluid; and
the amount of buffering agent is sufficient to protect at least a therapeutically effective amount of the proton pump inhibitor from acid degradation in the gastrointestinal fluid.
2 . The composition of claim 1 , wherein the proton pump inhibitor is selected from omeprazole, tenatoprazole, lansoprazole, rabeprazole, esomeprazole, pantoprazole, pariprazole, and leminoprazole, and a salt, an ester, a hydrate, an amide, an enantiomer, an isomer, a tautomer, a prodrug, a polymorph, or a derivative thereof.
3 . The composition of claim 1 , wherein the proton pump inhibitor is selected from omeprazole, lansoprazole, esomeprazole, and a salt, an ester, a hydrate, an amide, an enantiomer, an isomer, a tautomer, a prodrug, a polymorph, or a derivative thereof.
4 . The composition of claim 1 , wherein the proton pump inhibitor is in an amount of about 2 mg to about 300 mg.
5 . The composition of claim 2 , wherein the proton pump inhibitor is in an amount selected from 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, and 60 mg.
6 . The composition of claim 1 , wherein the proton pump inhibitor is micronized.
7 . The composition of claim 1 , wherein the composition is administered in an amount to achieve an initial serum concentration of the proton pump inhibitor greater than about 0.1 μg/ml at any time within about 1 hour after administration of the composition.
8 . The composition of claim 1 , wherein the composition is administered in an amount to maintain a serum concentration of the proton pump inhibitor greater than about 0.1 μg/ml from about 30 minutes after oral administration of the composition to a subject.
9 . The composition of claim 1 , wherein upon oral administration to a subject, the composition provides a pharmacokinetic profile such that at least about 50% of total area under serum concentration time curve (AUC) for the proton pump inhibitor occurs within about 1.5 hours after administration of a single dose of the composition to the subject.
10 . The composition of claim 1 , wherein upon oral administration to a subject, the composition provides a pharmacokinetic profile such that the proton pump inhibitor reaches a maximum serum concentration within about 1 hour after administration of a single dose of the composition.
11 . The composition of claim 1 , wherein the buffering agent is present in an amount to adjust the pH of the gastrointestinal fluid to between about 3 to about 8 after ingestion by a subject.
12 . The composition of claim 1 , wherein the at least one buffering agent is selected from aluminum hydroxide, aluminum hydroxide/magnesium carbonate, aluminum hydroxide/magnesium carbonate/calcium carbonate co-precipitate, aluminum magnesium hydroxide, aluminum hydroxide/magnesium hydroxide co-precipitate, aluminum hydroxide/sodium bicarbonate coprecipitate, calcium acetate, calcium bicarbonate, calcium borate, calcium carbonate, calcium citrate, calcium chloride, calcium glycerophosphate, calcium hydroxide, calcium lactate, calcium phthalate, calcium phosphate, calcium succinate, calcium tartrate, dibasic sodium phosphate, dipotassium hydrogen phosphate, dipotassium phosphate, disodium hydrogen phosphate, disodium succinate, dry aluminum hydroxide gel, magnesium acetate, magnesium aluminate, magnesium borate, magnesium bicarbonate, magnesium carbonate, magnesium citrate, magnesium hydroxide, magnesium lactate, magnesium metasilicate aluminate, magnesium oxide, magnesium phthalate, magnesium phosphate, magnesium silicate, magnesium succinate, magnesium tartrate, potassium acetate, potassium carbonate, potassium bicarbonate, potassium borate, potassium citrate, potassium metaphosphate, potassium phthalate, potassium phosphate, potassium polyphosphate, potassium pyrophosphate, potassium succinate, potassium tartrate, sodium acetate, sodium bicarbonate, sodium borate, sodium carbonate, sodium citrate, sodium dihydrogen phosphate, sodium hydrogen phosphate, sodium hydroxide, sodium lactate, sodium phthalate, sodium phosphate, sodium polyphosphate, sodium pyrophosphate, sodium sesquicarbonate, sodium succinate, sodium tartrate, sodium tripolyphosphate, synthetic hydrotalcite, tetrapotassium pyrophosphate, tetrasodium pyrophosphate, trihydroxymethylaminomethane, tripotassium phosphate, trisodium phosphate, and trometamol; and combinations thereof.
13 . The composition of claim 1 , wherein the at least one buffering agent is selected from sodium bicarbonate, sodium carbonate, calcium carbonate, magnesium oxide, magnesium hydroxide, magnesium carbonate, aluminum hydroxide, and mixtures thereof.
14 . The composition of claim 1 , wherein the at least one buffering agent is in an amount of at least about 2 mEq.
15 . The composition of claim 1 , wherein the at least one buffering agent is in an amount of about 2 mEq to about 40 mEq.
16 . The composition of claim 1 , wherein the at least one buffering agent is in an amount from about 250 mg to about 3000 mg.
17 . The composition of claim 1 , wherein the enteric coating comprises at least one of acetylatedmonoglyceride, carboxymethyl cellulose, cellulose acetate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose acetate trimellitate, cetyl alcohol, citric acid anhydrous, diethyl phthalate, diglyceride, ethyl cellulose, Eudragit® L-30D-55, Eudragit® NE30D, Eudragit® L 100, Eudragit® L 100-55, Eudragit® S100, Eudragit® FS 30 D, glyceryl monostearate, hydrogen peroxide, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, KollICoat® MAE30DP, Macrogel® 6000, methacrylic acid copolymer, monoglyceride, an organic acid, polyethylene glycol, polyethylene glycol 400, polyethylene glycol 6000, polymethacrylates containing carboxyl groups, polymethacrylates containing quaternary ammonium groups, polyquid PA-30, polysobate 80, polyvinyl acetate phthalate, polyvinyl alcohol, polyvinylpyrrolidone, a salt, shellac, sodium laurylsulphate, stearyl alcohol, a sugar, talc, triacetin, triethyl citrate, Tween® 80, a wax, or zein.
18 . The composition of claim 1 , wherein the enteric coating has a thickness of about 0.001 microns to about 100 microns.
19 . The composition of claim 1 , wherein the enteric coating has a thickness of about 0.01 microns to about 50 microns.
20 . The composition of claim 1 , wherein the enteric coating has a thickness less than about 25 microns.
21 . The composition of claim 1 , wherein the enteric coating has a thickness less than about 10 microns.
22 . The composition of claim 1 , wherein the enteric coating is a thickness that provides for release of at least 80% of the proton pump inhibitor in vitro within about 120 minutes.
23 . The composition of claim 1 , wherein the enteric coating is a thickness that provides for release of at least 80% of the proton pump inhibitor in vitro within about 60 minutes.
24 . The composition of claim 1 , wherein the enteric coating is a thickness that provides for release of at least 50% of the proton pump inhibitor in vitro within about 120 minutes
25 . The composition of claim 1 , wherein the enteric coating is a thickness that provides for release of at least 50% of the proton pump inhibitor in vitro within about 60 minutes.
26 . The composition of claim 1 , wherein the composition is in a pharmaceutical dosage form selected from a tablet, chewable tablet, caplet, a powder, a pill, a capsule, a lozenge, a sachet, a cachet, a troche, a minitab in a capsule, a pellet, and a granule.
27 . The composition of claim 1 , wherein the composition further comprises at least one of an excipient, a pharmaceutically compatible carrier, a binder, a filling agent, suspending agent, a taste masking agent, a flavoring agent, a sweetening agent, a disintegrant, a flow aid, a lubricant, an adjuvant, a colorant, a diluent, a solubilizer, a moistening agent, a stabilizer, a wetting agent, an anti-adherent, a glidant, a preservative, a parietal cell activator, an anti-foaming agent, an antioxidant, a chelating agent, an antifungal agent, an antibacterial agent, or an isotonic agent.
28 . A method of treating a condition or disorder where treatment with a proton pump inhibitor is indicated, the method comprising orally administering the composition according to claim 1 to a subject in need of such treatment.
29 . The method of claim 28 , wherein the gastrointestinal disorder is a duodenal ulcer disease, a gastric ulcer disease, a gastroesophageal reflux disease, an erosive esophagitis, a poorly responsive symptomatic gastroesophageal reflux disease, a pathological gastrointestinal hypersecretory disease, Zollinger Ellison Syndrome, acid dyspepsia, heartburn, an esophageal disorder, a non-erosive reflux disorder, or an NSAID induced ulcer.