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|Title:||Controlled release formulations having rapid onset and rapid decline of effective plasma drug concentrations|
|Abstract:||The invention is directed to oral modified/controlled release drug formulations which provide a rapid initial onset of effect and a prolonged duration of effect. Preferably, the peak concentration is lower than that provided by the reference standard for immediate release formulations of the drug, and the duration of effect falls rapidly at the end of the dosing interval.|
|Inventor(s):||Krishnamurthy; Thinnayam N. (Scarborough, CA), Darke; Andrew (Newmarket, CA)|
|Assignee:||Purdue Pharma (Pickering, Ontario, CA)|
1. An oral controlled release formulation which provides a rapid onset of therapeutic effect and a rapid drop in plasma concentration after a prolonged period of therapeutic
effect, comprising a plurality of matrix particulates comprising: a first portion of an effective dose of methylphenidate or a pharmaceutically acceptable salt thereof incorporated in a controlled release matrix, a hydrophobic material comprising an
acrylic polymer applied over the controlled release matrix in an amount sufficient to retard the release of the first portion of methylphenidate or a pharmaceutically acceptable salt thereof from the controlled release matrix; an enteric coating applied
over the hydrophobic material in an amount sufficient to substantially delay the release of said drug from said substrate until after said formulation passes through the stomach, wherein said enteric coating is derived from an aqueous dispersion
comprising an acrylic/methacrylic copolymer, a plasticizer and a glidant; and a topcoat comprising a second portion of the methylphenidate or a pharmaceutically acceptable salt thereof in immediate release form; wherein the formulation provides a time
to mean maximum plasma concentration of methylphenidate at about 0.5 to about 4 hours after oral administration.
2. The formulation of claim 1, wherein a unit dose comprises the matrix particulates contained within a gelatin capsule, and the second portion of the methyiphenidate or pharmaceutically acceptable salt thereof is contained within the gelatin capsule in a form selected from the group consisting of an immediate release powder, an immediate release granulate, immediate release matrix spheroids, immediate release beads, and as a coating applied onto the surface of the enteric coated matrix particulates.
3. The formulation of claim 1, wherein the matrix particulates are compressed into a tablet.
4. The formulation of claim 1, wherein the matrix particulates are subjected to oven curing at a temperature above the glass transition temperature of the acrylic polymer at a temperature from about 40 to about 500.degree.C for a time period of at least about 12 hours prior to the application of the enteric coating.
5. The formulation of claim 1, which provides a peak plasma concentration of methylphenidate which is from about 1.0 to about 2.0 times the plasma concentration of methylphenidate provided by the formulation at about 9 hours after oral administration.
6. The formulation of claim 5, wherein the duration of effect provided by methylphenidate falls below effective plasma concentrations at about 8 to about 12 hours after oral administration.
7. The formulation of claim 6, wherein the formulation provides a time to mean maximum plasma concentration at about 0.5 to about 2 hours after oral administration.
8. The formulation of claim 5, wherein the peak plasma concentration is from about 1.0 to about 1.7 times the plasma concentration of the methylphenidate provided by the formulation at about 9 hours after oral administration.
9. The formulation of claim 5, wherein the duration of effect provided by methylphenidate falls below effective plasma concentrations at about 8 to about 10 hours after oral administration.
10. The formulation of claim 9, which provides a "square wave" plasma profile.
11. The formulation of claim 9, which provides an in-vitro dissolution as follows: TABLE-US-00034 Time % Methylphenidate (hours) Dissolved 0.25 0-45% 1 5-50% 4 40-90% 8 NLT 60% 12 NLT 80%.
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