Controlled-release formulations coated with aqueous dispersions of ethylcellulose

A solid controlled release oral dosage formulation, comprising a substrate containing a systemically active therapeutic agent in an amount sufficient to provide a therapeutic effect when said formulation is orally administered, said substrate being coated with a cured aqueous dispersion of plasticized ethylcellulose to a weight gain from about 2% to about 25%, said coated substrate being cured at a temperature greater than the glass transition temperature of the aqueous dispersion of plasticized ethylcellulose and at a relative humidity from about 60% to about 100% for a sufficient period of time 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.degree. C. and at a relative humidity of 80% and said coating being sufficient to obtain a controlled release of said active agent when measured by the USP Paddle Method at 100 rpm at 900 ml aqueous buffer (pH between 1.6 and 7.2) at 37.degree. C. from about 12.5% 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 from about 55% to about 85% (by wt) active agent released after 8 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 20% of the total amount of therapeutically active agent released when compared to in-vitro dissolution conducted prior to storage.

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 plasticized ethylcellulose 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 ethylcellulose and at a relative humidity from about 60% to about 100% 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.degree. 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.

An oral solid dosage form comprising:

• a solid substrate comprising an effective amount of a therapeutically active agent,
• a coating covering said substrate, said coating comprising a cured aqueous dispersion of ethylcellulose in an amount required to provide effective blood levels of said therapeutically active agent for at least about 12 hours, said coated substrate being cured at a temperature greater than the glass transition temperature of the aqueous dispersion of plasticized ethylcellulose and at a relative humidity from about 60% to about 100% for a sufficient period of time 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.degree. C. and at a relative humidity of 80% and said coated substrate upon in-vitro dissolution testing providing a band range, when comparing the dissolution profile after exposure to accelerated storage conditions of at least one month at a temperature of 40.degree. C. and a relative humidity of 75% to the dissolution profile prior to exposure to said accelerated conditions, which is not wider than about 20% of total active agent released at any point of time.