Gastric retention dosage form having multiple layers

Abstract

The present invention is directed to a multilayered dosage form which is adapted for retention in the stomach and useful for the prolonged delivery of an active agent to a fluid environment of use. The active agent dosage form is a multilayer core, often bilayer, formed of polymer matrices that swell upon contact with the fluids of the stomach. At least one layer of the multilayered dosage form includes an active agent. A portion of the polymer matrices are surrounded by a band of insoluble material that prevents the covered portion of the polymer matrices from swelling and provides a segment of the dosage form that is of sufficient rigidity to withstand the contractions of the stomach and delay expulsion of the dosage form from the stomach until substantially all of the active agent has been dispensed.

1 . An active agent dosage form adapted for gastric retention comprising: 
 (a) a first layer comprising a swellable, water-soluble polymer;    (b) a second layer comprising a therapeutically-effective amount of an active agent, the second layer being laminated with the first layer at a common surface, and    (c) at least one band of insoluble material circumscribing and binding together the first layer and the second layer, the first layer being adapted to swell in the stomach to facilitate retention of the dosage form in the stomach over a prolonged period of time, wherein the release of the active agent from the second layer is independent of the composition of the first layer and occurs over a prolonged period of time.    
     
     
         2 . The active agent dosage form of  claim 1  wherein the number average molecular weight of the water-soluble polymer is between about 100,000 and 20,000,000 grams per mole.  
     
     
         3 . The active agent dosage form of  claim 2  wherein the water soluble polymer is polyethylene oxide, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, sodium carboxy methylcellulose, calcium carboxymethyl cellulose, methyl cellulose, polyacrylic acid, maltodextrin, pre-gelatinized starch, guar gum, sodium alginate, or polyvinyl alcohol.  
     
     
         4 . The active agent dosage form of  claim 1  wherein the second layer comprises a hydroattractant selected from low-substituted hydroxypropyl cellulose, microcrystalline cellulose, cross-linked sodium or calcium carboxymethyl cellulose, cellulose fiber, cross-linked polyvinyl pyrrolidone, cross-linked polyacrylic acid, cross-linked Amberlite resin, alginates, colloidal magnesium-aluminum silicate, corn starch granules, rice starch granules, potato starch granules and sodium carboxymethyl starch, sugars, sodium chloride, and the first layer optionally comprises a hydroattractant selected from low-substituted hydroxypropyl cellulose, microcrystalline cellulose, cross-linked sodium or calcium carboxymethyl cellulose, cellulose fiber, cross-linked polyvinyl pyrrolidone, cross-linked polyacrylic acid, cross-linked Amberlite resin, alginates, colloidal magnesium-aluminum silicate, corn starch granules, rice starch granules, potato starch granules, sodium carboxymethyl starch, sugars and sodium chloride.  
     
     
         5 . The active agent dosage form of  claim 1  wherein the first layer swells more rapidly and to a greater extent than does the second layer.  
     
     
         6 . The active agent dosage form of  claim 5  wherein the active agent is an antiviral, antimicrobial, antidiabetic, antihperglycemic, hypoglycemic, antidepressant, antiobesity or antifungal active agent.  
     
     
         7 . The active agent dosage form of  claim 4  wherein the weight percent of the water soluble polymer in the second layer is 5 to 99.99 weight percent and weight percent of the hydroattractant in the second layer is 0 to 60 weight percent.  
     
     
         8 . The active agent dosage form of  claim 1  wherein the prolonged time period is at least 3 hours.  
     
     
         9 . The active agent dosage form of  claim 1  wherein the time period is between about 6 to 12 hours.  
     
     
         10 . The dosage form of  claim 1  wherein the first layer comprises polyethylene oxide having a number average molecular weight of at least 100,000 grams per mole.  
     
     
         11 . The dosage form of  claim 10  wherein the active agent is an antiviral, antimicrobial, antidiabetic, antihperglycemic, hypoglycemic, antidepressant, antiobesity or antifungal active agent.  
     
     
         12 . The dosage form of  claim 11  wherein the active agent is acyclovir, ganciclovir, ritonavir, minocycline, cimetidine, ranitidine, captopril, methyldopa, selegiline, minocycline, fexofenadine, metformin, bupropion, orlistat or a pharmaceutically acceptable salt thereof.  
     
     
         13 . The dosage form of  claim 10  wherein the active agent is metformin or a pharmaceutically acceptable salt thereof.  
     
     
         14 . The dosage dosage form of  claim 1  wherein the second layer comprises an active agent selected from the group consisting of acyclovir, ganciclovir, ritonavir, metformin, bupropion, orlistat and minocycline, and the second layer comprises a bioerodible polymer, wherein the dosage form releases a therapeutically effective amount of the active agent to the stomach of a subject over at least a 3 hour period.  
     
     
         15 . A method of treating a subject in need thereof with an active agent that comprises administering to the subject a multilayered dosage form adapted to be retained in the stomach over a prolonged period of time, the dosage form comprising a first layer adapted to swell in the stomach of the subject and retain the dosage form in the stomach for a prolonged period of time, and a second layer adapted to deliver to the subject an active agent at a variable rate of delivery.  
     
     
         16 . The method of  claim 15  which comprises administering one or more dosage forms to the subject in the fed state at the start of each dosing period.  
     
     
         17 . The method of  claim 16  wherein the administration of the dosage form occurs within one hour of the subject consuming food.  
     
     
         18 . The dosage form of  claim 1  comprising a gastric-emptying delaying agent.  
     
     
         19 . The dosage form of  claim 18  wherein the gastric-emptying delaying agent is selected from anticholonergic agents, methylcellulose, guar gum, fats and fatty acids of 10-15 carbon atoms.  
     
     
         20 . The dosage form of  claim 1  wherein the active agent comprises a liquid, active agent formulation.  
     
     
         21 . The dosage form of  claim 20  wherein the liquid, active agent formulation is sorbed into porous particles.  
     
     
         22 . The dosage form of  claim 21  wherein the porous particles are calcium hydrogen phosphate or magnesium aluminometasilicate.  
     
     
         23 . The dosage form of  claim 1  wherein the dosage form comprises a pH regulating agent.  
     
     
         24 . The dosage form of  claim 21  wherein the liquid, active agent formulation comprises a pH regulating agent selected from organic and inorganic acids and bases.  
     
     
         25 . The dosage form of  claim 21  wherein the liquid, active agent formulation comprises a chelating agent.