Sustained release of guaifenesin

Abstract

The invention relates to a novel pharmaceutical sustained release formulation of guaifenesin. The formulation may comprise a hydrophilic polymer, preferably a hydroxypropyl methylcellulose, and a water-insoluble polymer, preferably an acrylic resin, in a ratio range of about one-to-one (1:1) to about nine-to-one (9:1), more preferably a range of about three-to-two (3:2) to about six-to-one (6:1), and most preferably in a range of about two-to-one (2:1) to about four-to-one (4:1) by weight. This formulation capable of providing therapeutically effective bioavailability of guaifenesin for at least twelve hours after dosing in a human subject. The invention also relates to a modified release product which has two portions: a first portion having an immediate release formulation of guaifenesin and a second portion having a sustained release formulation of guaifenesin. The modified release product has a maximum guaifenesin serum concentration equivalent to that of an immediate release guaifenesin tablet, and is capable of providing therapeutically effective bioavailability of guaifenesin for at least twelve hours after dosing in a human subject.

1 - 36 . (canceled) 
     
     
         37 . A single dose drug product, comprising:
 1200 mg total guaifenesin in both first and second portions;   said first portion being an immediate release form that releases said guaifenesin in a human subject's stomach; and   said second portion being in a sustained release form that releases said guaifenesin in a human patient's intestine, said sustained release form being a matrix comprising 0.5-4.0 wt % of a hydrophilic polymer and a water-insoluble polymer having said second portion of guaifenesin admixed therein, said hydrophilic polymer and said water-insoluble polymer being present in a weight ratio of from 1:1 to 9:1, said hydrophilic polymer being selected from the group consisting of acacia, gum tragacanth, locust bean gum, guar gum, karaya gum, methylcellulose, hydroxymethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethylcellulose, carboxymethylcellulose, agar, pectin, carrageen, alginate, carboxypolymethylene, gelatin, casein, zein, bentonite, magnesium aluminum silicate, polysaccharide, modified starch derivative and combinations thereof, and said water-insoluble polymer being selected from the group consisting of polyacrylic acids, acrylic resins, acrylic latex dispersions, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate and combinations thereof, wherein   from 63% to 72% of said total amount of guaifenesin is absorbed into said human subject's bloodstream within 3 hours after administration under fasted conditions,   guaifenesin is absorbed into the bloodstream such that the single dose drug product can be appropriately dosed once in a 12-hour period, and   said single dose drug product optionally comprising at least one additional drug selected from the group consisting of an antitussive, a decongestant, an antihistamine, an analgesic and combinations thereof.   
     
     
         38 . The drug product according to  claim 37 , wherein from 67% to 72% of the total amount of guaifenesin absorbed into the bloodstream is absorbed within 3 hours after administration under fasted conditions. 
     
     
         39 . The drug product according to  claim 37 , wherein 63% of the total amount of guaifenesin absorbed into the bloodstream is absorbed within 3 hours after administration under fasted conditions. 
     
     
         40 . The drug product according to  claim 37 , wherein 67% of the total amount of guaifenesin absorbed into the bloodstream is absorbed within 3 hours after administration under fasted conditions. 
     
     
         41 . The drug product according to  claim 37 , wherein 72% of the total amount of guaifenesin absorbed into the bloodstream is absorbed within 3 hours after administration under fasted conditions. 
     
     
         42 . The drug product according to  claim 37 , wherein the first and second portions are discrete. 
     
     
         43 . The drug product according to  claim 42 , which is in a form of a bi-layer tablet. 
     
     
         44 . The drug product according to  claim 42 , wherein said first and second portions are both in the form of beads or granules. 
     
     
         45 . The drug product according to  claim 42 , wherein said hydrophilic polymer and said water-insoluble polymer are present in a weight ratio of from 3:2 to 6:1. 
     
     
         46 . The drug product according to  claim 42 , wherein said hydrophilic polymer and said water-insoluble polymer are present in a weight ratio of from 2:1 to 4:1. 
     
     
         47 . The drug product according to  claim 37 , which comprises more than 0.5 and less than 10 total wt. % of said hydrophilic polymer. 
     
     
         48 . The drug product according to  claim 45 , which comprises more than 1 and less than 7 total wt. % of said hydrophilic polymer. 
     
     
         49 . The drug product according to  claim 46 , which comprises more than 2 and less than 6 total wt. % of said hydrophilic polymer. 
     
     
         50 . The drug product according to  claim 47 , which comprises more than 0.5 and less than 2.5 total wt. % of said water insoluble polymer. 
     
     
         51 . The drug product according to  claim 48 , which comprises more than 0.75 and less than 1.5 total wt. % of said water insoluble polymer. 
     
     
         52 . The drug product according to  claim 49 , which comprises more than 0.9 and less than 1.25 total wt. % of said water insoluble polymer. 
     
     
         53 . The drug product according to  claim 51 , wherein said matrix comprises 1 to 2 wt. % of said hydrophilic polymer. 
     
     
         54 . The drug product according to  claim 52 , wherein said matrix comprises 1 to 2 wt. % of said hydrophilic polymer. 
     
     
         55 . The drug product according to  claim 45 , wherein said hydrophilic polymer is selected from the group consisting of methylcellulose, hydroxymethylcellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethylcellulose, carboxymethyl cellulose and combinations thereof. 
     
     
         56 . The drug product according to  claim 46 , wherein said hydrophilic polymer comprises hydroxypropyl methylcellulose. 
     
     
         57 . The drug product according to  claim 54 , wherein said hydrophilic polymer is selected from the group consisting of methylcellulose, hydroxymethylcellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethylcellulose, carboxymethyl cellulose and combinations thereof. 
     
     
         58 . The drug product according to  claim 57 , wherein said sustained release form comprises 75 to 95 weight percent guaifenesin. 
     
     
         59 . The drug product according to  claim 58 , wherein said immediate release form comprises 47 to 58 weight percent guaifenesin. 
     
     
         60 . The drug product according to  claim 59 , wherein said sustained release form comprises 75 to 80 weight percent guaifenesin. 
     
     
         61 . The drug product according to  claim 60 , comprising said additional drug, wherein said additional drug is selected from the group consisting of dextromethorphan hydrobromide, codeine, hydrocodone, phenylephrine hydrochloride, phenylpropanolamine hydrochloride, pseudoephedrine hydrochloride, ephedrine, chlorpheniramine maleate, brompheniramine maleate, phenindamine tartrate, pyrilamine maleate, doxylamine succinate, phenyltoloxamine citrate, diphenhydramine hydrochloride, promethazine, clemastine fumarate, aspirin, ibuprofen, naprosin, acetaminophen and combinations thereof. 
     
     
         62 . The drug product according to  claim 61 , wherein said additional drug is contained within said sustained release form. 
     
     
         63 . The drug product according to  claim 61 , wherein said additional drug is contained within said immediate release form. 
     
     
         64 . The drug product according to  claim 61 , wherein the ratio of total guaifenesin to said at least one additional drug is 1:1 to 20:1 by weight. 
     
     
         65 . The drug product according to  claim 64 , wherein the ratio of total guaifenesin to said at least one additional drug is 2:1 to 15:1 by weight. 
     
     
         66 . The drug product according to  claim 65 , wherein the ratio of total guaifenesin to said at least one additional drug is 8:1 to 12:1 by weight. 
     
     
         67 . The drug product according to  claim 37 , wherein the ratio of guaifenesin in the sustained release form to the guaifenesin in the immediate release form is 1:1 to 15:1 by weight. 
     
     
         68 . The drug product according to  claim 67 , wherein the ratio of guaifenesin in the sustained release form to the guaifenesin in the immediate release form is 3:2 to 11:1 by weight. 
     
     
         69 . The drug product according to  claim 68 , wherein the ratio of guaifenesin in the sustained release form to the guaifenesin in the immediate release form is 5:1 to 9:1 by weight. 
     
     
         70 . The drug product according to  claim 67 , wherein the ratio of said at least one additional drug in the sustained release form to said at least one additional drug in the immediate release form is 1:1 to 19:1 by weight. 
     
     
         71 . The drug product according to  claim 68 , wherein the ratio of said at least one additional drug in the sustained release form to said at least one additional drug in the immediate release form is 3:2 to 9:1 by weight. 
     
     
         72 . The drug product according to  claim 69 , wherein the ratio of said at least one additional drug in the sustained release form to said at least one additional drug in the immediate release form is 3:1 to 4:1 by weight.