Composition and dosage form for delayed gastric release of alendronate and/or other bis-phosphonates

Abstract

The present invention provides a compacted pharmaceutical composition for oral administration to a patient which expands upon contact with gastric fluid to retain a dosage form in the patient's stomach for an extended period of time, the formulation comprising a non-hydrated hydrogel, a superdisintegrant and tannic acid. The present invention further provides a pharmaceutical dosage form containing an active ingredient, and the compacted pharmaceutical composition. The invention further provides a dosage form suitable for delivering a therapeutic bis-phosphonate such as alendronate to the stomach of a patient over and extended period

We claim:  
     
         1 . A pharmaceutical dosage form for oral administration to a patient which provides delayed gastric release of a therapeutically effective amount of a therapeutic bis-phosphonate, the dosage form comprising the bis-phosphonate and a drug delivery vehicle comprising a non-hydrated hydrogel wherein upon contact with gastric fluid or simulated gastric fluid the non-hydrated hydrogel hydrates and the delivery vehicle expands.  
     
     
         2 . The pharmaceutical dosage form of  claim 1  wherein the drug delivery vehicle further comprises a superdisintegrant.  
     
     
         3 . The pharmaceutical dosage form of  claim 2  wherein the drug delivery vehicle further comprises tannic acid.  
     
     
         4 . The pharmaceutical dosage form of  claim 1  wherein release of substantial amounts of the bis-phosphonate is delayed for a period of two hours or more.  
     
     
         5 . The pharmaceutical dosage form of  claim 1  wherein release of substantial amounts of the bis-phosphonate is delayed for a period of three hours or more.  
     
     
         6 . The pharmaceutical dosage form of  claim 1  wherein release of substantial amounts of the bis-phosphonate is delayed for a period of four hours or more.  
     
     
         7 . The pharmaceutical dosage form of  claim 1  wherein the bis-phosphonate is selected from the group consisting of alendronic acid and its pharmaceutically acceptable salts and hydrates thereof, residronate, etidronate and teludronate.  
     
     
         8 . The pharmaceutical dosage form of  claim 1  wherein the bis-phosphonate is alendronic acid or one of its pharmaceutically acceptable salts and hydrates thereof.  
     
     
         9 . The pharmaceutical dosage form of  claim 8  wherein the bis-phosphonate is monosodium alendronate monohydrate.  
     
     
         10 . The pharmaceutical dosage form of  claim 8  wherein the bis-phosphonate is monosodium alendronate trihydrate.  
     
     
         11 . The pharmaceutical dosage form of  claim 8  wherein the bis-phosphonate is alendronic acid.  
     
     
         12 . The pharmaceutical dosage form of  claim 1  wherein the hydrogel comprises hydroxypropyl methylcellulose.  
     
     
         13 . The pharmaceutical dosage form of  claim 12  wherein the hydrogel further comprises hydroxypropyl cellulose.  
     
     
         14 . The pharmaceutical dosage form of  claim 13  wherein the hydrogel comprises hydroxypropyl methylcellulose and hydroxypropyl cellulose in a weight ratio of from about 1:3 to about 5:3.  
     
     
         15 . The pharmaceutical dosage form of  claim 2  wherein the superdisintegrant is selected from the group consisting of cross-linked polyvinylpyrrolidone, cross-linked carboxymethyl cellulose sodium and sodium starch glycolate.  
     
     
         16 . The pharmaceutical dosage form of  claim 15  wherein the superdisintegrant is sodium starch glycolate.  
     
     
         17 . The pharmaceutical dosage form of  claim 15  wherein the superdisintegrant is cross-linked carboxymethyl cellulose sodium.  
     
     
         18 . The pharmaceutical dosage form of  claim 3  wherein tannic acid comprises from about 5 weight percent to about 15 weight percent of the drug delivery vehicle.  
     
     
         19 . A method of treating bone disease in a human patient in need of such treatment by administering to the patient the pharmaceutical dosage form of  claim 1 .  
     
     
         20 . The method of  claim 19  wherein the bone disease is metastatic bone disease.  
     
     
         21 . The method of  claim 19  wherein the bone disease is osteoporosis.  
     
     
         22 . The method of  claim 19  wherein the bone disease is Paget's disease.  
     
     
         23 . A method of inhibiting bone resorption in a human patient in need of such treatment by administering to the patient the pharmaceutical dosage form of  claim 1 .  
     
     
         24 . A method of treating hypercalcemia in a human patient in need of such treatment by administering to the patient the pharmaceutical dosage form of  claim 1 .  
     
     
         25 . A method of treating malignancy in bone of a human patient in need of such treatment by administering to the patient the pharmaceutical dosage form of  claim 1 .  
     
     
         26 . The pharmaceutical dosage form of  claim 1  wherein the drug delivery vehicle comprises of from about 50 wt. % to about 80 wt. % of a hydrogel, of from about 10 wt. % to about 30 wt. % of a superdisintegrant, and of from about 5 wt. % to about 10 wt. % tannic acid.  
     
     
         27 . The pharmaceutical dosage form of  claim 26  capable of being retained in the stomach of a human patient for a period of at least two hours.  
     
     
         28 . The pharmaceutical dosage form of  claim 26  capable of being retained in the stomach of a human patient for a period of at least three hours.  
     
     
         29 . The pharmaceutical dosage form of  claim 26  wherein the dosage form swells by a factor of five or more within about fifteen minutes of contacting aqueous solution.  
     
     
         30 . The pharmaceutical dosage form of  claim 29  wherein the dosage form swells by a factor of eight or more within about fifteen minutes of contacting aqueous solution.  
     
     
         31 . The pharmaceutical dosage form of  claim 29  wherein the dosage form swells by a factor of five or more within about five minutes of contacting aqueous solution.  
     
     
         32 . The pharmaceutical dosage form of  claim 26  further comprising a substance that emits gas upon contact with acid.  
     
     
         33 . The pharmaceutical dosage form of  claim 32  wherein the substance that emits gas upon contact with acid is sodium bicarbonate.  
     
     
         34 . The pharmaceutical dosage form of  claim 26  wherein the hydrogel comprises hydroxypropyl methylcellulose.  
     
     
         35 . The pharmaceutical dosage form of  claim 34  wherein the hydrogel further comprises hydroxypropyl cellulose.  
     
     
         36 . The pharmaceutical dosage form of  claim 35  wherein the hydrogel comprises hydroxypropyl methylcellulose and hydroxypropyl cellulose in a weight ratio of from about 1:3 to about 5:3.  
     
     
         37 . The pharmaceutical dosage form of  claim 26  wherein the superdisintegrant is selected form the group consisting of cross-linked polyvinylpyrrolidone, cross-linked carboxymethyl cellulose sodium and sodium starch glycolate.  
     
     
         38 . A coated pharmaceutical dosage form comprising a core which contains a therapeutic bis-phosphonate and optionally other pharmaceutical excipients and a coating around the core, wherein the coating comprises a hydrogel, a superdisintegrant and tannic acid.  
     
     
         39 . The coated pharmaceutical dosage form of  claim 38  from about 50 wt. % to about 80 wt. % of a hydrogel, from about 10 wt. % to about 30 wt. % of a superdisintegrant, and from about 5 wt. % to about 10 wt. % tannic acid.  
     
     
         40 . A coated pharmaceutical dosage form having a core comprising about 18 wt. % sodium alendronate monohydrate, about 48 wt. % microcrystalline cellulose and about 32 wt. % lactose, the core having a coating thereon which comprises about 17 wt. % HPMC, about 10 wt. % tannic acid, about 50 wt. % HPC and about 22 wt. % crosslinked carboxymethyl cellulose sodium.  
     
     
         41 . A coated pharmaceutical dosage form having a core comprising about 18 wt. % sodium alendronate monohydrate, about 41 wt. % microcrystalline cellulose and about 41 wt. % lactose, the core having a coating thereon which comprises about 17 wt. % HPMC, about 10 wt. % tannic acid, about 50 wt. % HPC and about 22 wt. % crosslinked carboxymethyl cellulose sodium.  
     
     
         42 . A method of making the dosage form of  claim 40  or  41  comprising the steps of mixing powdered sodium alendronate monohydrate, microcrystalline cellulose and lactose, tableting the mixed powders to make a core, dry mixing the HPMC, tannic acid, HPC and cross-linked carboxymethyl sodium to produce a coating mix, embedding the core in the coating mix and compacting the coating mix to produce the dosage form.