Controlled release formulations coated with aqueous dispersions of acrylic polymers
AssigneeEuro-Celtique S.A.
InventorsBenjamin Oshlack, Frank Pedi, Jr., Mark Chasin
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Abstract
A stable solid controlled release formulation having a coating derived from an aqueous dispersion of a hydrophobic acrylic polymer includes a substrate including an active agent selected from the group consisting of a systemically active therapeutic agent, a locally active therapeutic agent, a disinfecting and sanitizing agent, a cleansing agent, a fragrance agent and a fertilizing agent, overcoated with an aqueous dispersion of the plasticized water-insoluble acrylic polymer. The formulation provides a stable dissolution of the active agent which is unchanged after exposure to accelerated storage conditions.
Claims56
A controlled release formulation comprising a substrate containing an active agent in an amount sufficient to provide a desired effect in an environment of use, said substrate coated with a plasticized aqueous dispersion consisting essentially of ammoniomethacrylate copolymers which are copolymerizates of acrylic and methacrylic esters having a low content of quaternary ammonium groups in an amount sufficient to obtain a controlled release of said active agent when said formulation is exposed to an environmental fluid, said coated substrate being cured at a temperature greater than the glass transition temperature of the aqueous dispersion of said plasticized water-insoluble acrylic polymer for about 24 to about 60 hours until a curing endpoint is reached at which said cured coated substrate provides a stabilized dissolution of said active agent which is unchanged after exposure to accelerated storage conditions, said endpoint being determined by comparing the dissolution profile of the formulation immediately after curing to the dissolution profile of the formulation after exposure to accelerated storage conditions of at least one month at a temperature of 37.degree. C. and at a relative humidity of 80%.
The formulation of claim 6, wherein said systemically active therapeutic agent is selected from the group consisting of antihistamines, analgesics, non-steroidal anti-inflammatory agents, gastro-intestinals, anti-emetics, anti-epileptics, vasodilators, anti-tussive agents, expectorants, anti-asthmatics, hormones, diuretics, anti-hypotensives, anti-hypertensives, bronchodilators, antibiotics, antivirals, antihemorrhoidals, steroids, hypnotics, psychotropics, antidiarrheals, mucolytics, sedatives, decongestants, laxatives, vitamins, and stimulants.
A solid controlled release formulation, comprising a substrate containing an active agent in an amount sufficient to provide a desired effect in an environment of use, said substrate coated with a plasticized aqueous dispersion consisting essentially of ammoniomethacrylate copolymers which are copolymerizates of acrylic and methacrylic esters having a low content of quaternary ammonium groups in an amount sufficient to obtain a controlled release of said active agent when said formulation is exposed to an environmental fluid, said coated substrate being cured at a temperature greater than the glass transition temperature of the plasticized water-insoluble acrylic polymer for about 24 to about 60 hours until an endpoint is reached at which said cured coated substrate, when exposed to an environment of use, releases said active agent in amounts which do not vary at any time point along the dissolution curve by more than about 15% of the total amount of active agent released, when compared to the in-vitro dissolution of said coated substrate prior to curing.
A solid controlled release oral dosage formulation, comprising a substrate containing a systemically active therapeutic agent in an amount sufficient to provide a desired therapeutic effect when said formulation is orally administered, said substrate being coated with an aqueous dispersion consisting, essentially of a plasticized copolymer of acrylic and methacrylic acid esters having a permeability which is unaffected by the pH conditions prevailing in the digestive tract, to a weight gain sufficient to obtain a controlled release of said active agent when measured by the USP Paddle or Basket Method at 100 rpm at 900 ml aqueous buffer (pH between 6 and 7.2) at 37.degree. C. from about 0% to about 42.5% (by wt) active agent released after 1 hour, from about 25% to about 55% (by wt) active agent released after 2 hours, from about 45% to about 75% (by wt) active agent released after 4 hours and greater than about 55% (by wt) active agent released after 6 hours, said coated substrate being cured at a temperature greater than the glass transition temperature of said aqueous dispersion of the plasticized acrylic polymer for a time period of about 20 to about 60 hours, said coated substrate when subjected to accelerated storage conditions of at least one month at 40.degree. C./75% RH releasing an amount of said therapeutically active agent upon in-vitro dissolution which does not vary at any given time point by more than about 15% of the total amount of therapeutically active agent released when compared to in-vitro dissolution conducted prior to storage, and when administered orally providing effective blood levels of said systemically active therapeutic agent for at least about 12 hours.
A solid controlled release oral dosage formulation, comprising a substrate containing a systemically active therapeutic agent in an amount sufficient to provide a desired therapeutic effect when said formulation is orally administered, said substrate being coated with an aqueous dispersion consisting essentially of a plasticized copolymer of acrylic and methacrylic acid esters having a permeability which is unaffected by the pH conditions prevailing in the digestive tract, to a weight gain sufficient to obtain a controlled release of said active agent when measured by the USP Paddle or Basket Method at 100 rpm at 900 ml aqueous buffer (pH between 1.6 and 7.2) at 37.degree. C. from about 0% to about 42.5% (by wt) active agent released after 1 hour, from about 5% to about 60% (by wt) active agent released after 2 hours, from about 15% to about 75% (by wt) active agent released after 4 hours and from about 20% to about 90% (by wt) active agent released after 8 hours, said coated substrate being cured at a temperature greater than the glass transition temperature of said aqueous dispersion of the plasticized acrylic polymer for a time period of about 20 to about 60 hours, said coated substrate when subjected to accelerated storage conditions of at least one month at 40.degree. C./75% RH releasing an amount of said therapeutically active agent upon in-vitro dissolution which does not vary at any given time point by more than about 15% of the total amount of therapeutically active agent released when compared to in-vitro dissolution conducted prior to storage, and when administered orally providing effective blood levels of said systemically active therapeutic agent for about 24 hours.
A solid controlled release formulation, comprising a substrate containing an active agent in an amount sufficient to provide a desired effect in an environment of use, said substrate coated with an aqueous dispersion consisting essentially of a plasticized water-insoluble acrylic polymer comprised of monomers selected from the group consisting of an ester of acrylic acid, an ester of methacrylic acid, an alkyl ester of acrylic acid, an alkyl ester of methacrylic acid, and mixtures of any of the foregoing, in an amount sufficient to obtain a controlled release of said active agent when said formulation is exposed to an environmental fluid, said coated substrate including at least one passageway through said coating through which said active agent is released, said coated substrate being cured at a temperature greater than the glass transition temperature of the plasticized aqueous dispersion for a time period of about 20 to about 60 hours until an endpoint is reached at which said cured coated substrate, when subjected to in-vitro dissolution, releases said active agent in amounts which do not vary at any time point along the dissolution curve by more than about 15% of the total amount of active agent released, when compared to the in-vitro dissolution of said coated substrate prior to curing.
A controlled release dosage form, comprising a solid substrate comprising an effective amount of a therapeutically active agent, said solid substrate coated with an aqueous dispersion consisting essentially of a copolymer of acrylic and methacrylic acid esters having a low content of quaternary ammonium groups, in an amount effective to provide a controlled release of said therapeutically active agent when said coated substrate is exposed to gastrointestinal fluid, said coated substrate being cured at a temperature greater than the glass transition temperature of said aqueous dispersion of the plasticized acrylic polymer for a time period of about 20 to about 60 hours, said coated substrate when subjected to in-vitro dissolution after exposure to accelerated storage conditions of at least one month at 40.degree. C./75% RH releasing an amount of said therapeutically active agent which does not vary at any given dissolution time point by more than about 15% of the total amount of therapeutically active agent released when compared to in-vitro dissolution conducted prior to storage.
Dependencies are inferred from the claim text.