Controlled release formulations coated with aqueous dispersions of acrylic polymers

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 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 Baslcet Method at 100 rpm at 900 ml aqueous buffer (pH between 1.6 and 7.2) at 37° 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 when subjected to accelerated storage conditions of at least one month at 40° 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 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° 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 when subjected to accelerated storage conditions of at least one month at 40° 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 method of treating a patient with a controlled release oral solid dosage form which provides an effective blood level of a therapeutically active agent for a predetermined amount of time, comprising:

• preparing a solid substrate comprising a sufficient amount of a therapeutically active agent to provide therapeutically effective blood levels in the patient for about 12 to about 24 hours,
• coating said substrate with a sufficient amount an aqueous dispersion of a plasticized water-insoluble copolymer of acrylic and methacrylic acid esters having a permeability which is unaffected by the pH conditions prevailing in the digestive tract, to obtain a predetermined controlled release of said active agent when said coated substrate is exposed to an environmental fluid, and
• curing said coated substrate at a temperature greater than the glass transition temperature of the plasticized aqueous dispersion until a curing endpoint is reached at which said 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° C. and at a relative humidity of 80%,
• and administering an oral solid dosage form comprising said cured, coated substrate to the patient to thereby obtain the desired therapeutic effect for about 12 to about 24 hours.

A method for obtaining an controlled release formulation of an active agent, comprising:

• preparing a solid substrate comprising an active agent;
• coating said substrate with a sufficient amount an aqueous dispersion of (i) 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, and (ii) a further material selected from the group consisting of a polymerizable permeability-enhancing agent, a water-soluble acrylic polymer, a pore-former, and mixtures of any of the foregoing, to obtain a predetermined controlled release of said active agent when said coated substrate is exposed to an environmental fluid, and
• curing said coated substrate at a temperature greater than the glass transition temperature of the aqueous dispersion of plasticized water-insoluble acrylic polymer until a curing endpoint is reached at which said coated substrate upon exposure to an environmental fluid provides a band range, when comparing the dissolution profile after exposure to accelerated storage conditions of at least one month at 40° C./75% RH to the dissolution profile prior to exposure of said coated substrate to said accelerated conditions, which is not wider than about 15% of total active agent released at any point of time during said dissolution.