Shell-and-core dosage form approaching zero-order drug release

Abstract

Drugs are formulated as oral dosage forms for controlled release in which the release rate limiting portion is a shell surrounding the drug-containing core. The shell releases drug from the core by permitting diffusion of the drug from the core. The shell also motes gastric retention of the dosage form by swelling upon imbibition of gastric fluid to size that is retained in the stomach during the postprandial or fed mode.

What is claimed is: 
     
         1 . A controlled-release oral drug dosage form for releasing a drug into at least a portion of a region defined by the stomach and the upper gastrointestinal tract, said dosage form comprising:
 (a) a core comprising a first solid polymeric matrix with said drug dispersed therein, and   (b) a shell substantially completely encasing said core, said shell comprising a second solid polymeric matrix that swells upon imbibition of water to a size large enough to promote retention in the stomach while the stomach is in a fed mode, and said shell having a drug:polymer weight ratio that is substantially less than that of said core,   said shell having a thickness that is at least about 0.5% of the longest linear dimension of said dosage form, said second polymeric matrix being of a material and thickness relative to said core such that when said dosage form is immersed in gastric fluid, said drug is released from said dosage form into said gastric fluid at a controlled rate limited at least in part by diffusion of said drug through said shell to an extent that at least about 40% of said drug remains unreleased one hour after such immersion has begun and substantially all of said drug is released within about twenty-four hours after such immersion has begun.   
     
     
         2 . A controlled-release oral drug dosage form in accordance with  claim 1 , wherein said core has an outer surface and said shell has an inner surface in full contact with said outer surface of said core. 
     
     
         3 . A controlled-release oral drug dosage form in accordance with  claim 1 , wherein said shell thickness is from about 1% to about 60% of the longest linear dimension of said dosage form. 
     
     
         4 . A controlled release oral drug dosage form in accordance with  claim 1 , wherein the drug:polymer weight ratio of said shell is equal to or less than about 0.5 times the drug:polymer weight ratio of said core. 
     
     
         5 . A controlled release oral drug dosage form in accordance with  claim 1 , wherein said shell contains substantially none of said drug. 
     
     
         6 . A controlled-release oral drug dosage form in accordance with  claim 1 , wherein said oral drug dosage form is a tablet having a total weight of from about 50 mg to about 5000 mg. 
     
     
         7 . A controlled-release oral drug dosage form in accordance with  claim 1 , wherein said first and second polymeric matrices are formed of polymers independently selected from the group consisting of poly(ethylene oxide), poly(vinyl alcohol), cellulose, alkyl-substituted cellulose, hydroxyalkyl-substituted cellulose, crosslinked polyacrylic acids, and xanthan gum. 
     
     
         8 . A controlled-release oral drug dosage form in accordance with  claim 1 , wherein said first and second polymeric matrices are formed of polymers independently selected from the group consisting of poly(ethylene oxide), hydroxypropylmethyl cellulose, and hydroxyethyl cellulose. 
     
     
         9 . A controlled-release oral drug dosage form in accordance with  claim 1 , wherein said first and second polymeric matrices are both poly(ethylene oxide). 
     
     
         10 . A controlled-release oral drug dosage form in accordance with  claim 9 , wherein said poly(ethylene oxide) has a molecular weight of at least about 2,000,000. 
     
     
         11 . A controlled-release oral drug dosage form in accordance with  claim 9 , wherein said poly(ethylene oxide) of said first polymeric matrix has a higher molecular weight than said poly(ethylene oxide) of said second polymeric matrix. 
     
     
         12 . A controlled-release oral drug dosage form in accordance with  claim 11 , wherein the molecular weight ratio of said poly(ethylene oxide) of said first polymeric matrix to said poly(ethylene oxide) of said second polymeric matrix is from about 1.15:1 to about 2.5:1. 
     
     
         13 . A controlled-release oral drug dosage form in accordance with  claim 1 , wherein the amount of said drug in said core is from about 1% to about 98% by weight. 
     
     
         14 . A controlled-release oral drug dosage form in accordance with  claim 1 , wherein said second polymeric matrix is of a material and volume relative to said core that at least about 60% of said drug remains unreleased two hours after such immersion has begun. 
     
     
         15 . A controlled-release oral drug dosage form in accordance with  claim 1 , wherein said drug is a member selected from the group consisting of metformin hydrochloride, vancomycin hydrochloride, captopril, lisinopril, erythromycin lactobionate, acyclovir, ranitidine hydrochloride, baclofen, sertraline hydrochloride, levodopa, tramadol, and ticlopidine hydrochloride. 
     
     
         16 . A controlled-release oral drug dosage form in accordance with  claim 1 , wherein said drug is a member selected from the group consisting of amoxicillin, cefuroxime axetil, cefaclor, clindamycin, clarithromycin, azithromycin, ceftazidime, and ciprofloxacin. 
     
     
         17 . A controlled-release oral drug dosage form in accordance with  claim 1 , wherein said drug is a member selected from the group consisting of cyclosporine, digoxin, doxifluridine, and paclitaxel. 
     
     
         18 . A controlled-release oral drug dosage form in accordance with  claim 1 , wherein 
     
     
         19 . A controlled-release oral drug dosage form in accordance with  claim 1 , wherein said drug is nelfinar mesylate. 
     
     
         20 . A method for administering a drug to a subject comprising,
 orally administering a controlled-release oral drug dosage form, wherein the dosage form comprises:   (a) a core comprising a first solid polymeric matrix with said drug dispersed therein, and   (b) a shell substantially completely encasing said core, said shell comprising a second solid polymeric matrix that swells upon imbibition of water to a size large enough to promote retention in the stomach while the stomach is in a fed mode, and said shell having a drug:polymer weight ratio that is substantially less than that of said core, said shell having a thickness that is at least about 0.5% of the longest linear dimension of said dosage form, said second polymeric matrix being of a material and thickness relative to said core such that when said dosage form is immersed in gastric fluid, said drug is released from said dosage form into said gastric fluid at a controlled rate limited at least in part by diffusion of said drug through said shell to an extent that at least about 40% of said drug remains unreleased one hour after such immersion has begun and substantially all of said drug is released within about twenty-four hours after such immersion has begun.