Controlled release formulations having rapid onset and rapid decline of effective plasma drug concentrations

• US 6,419,960 B1
• Filed: 12/16/1999
• Issued: 07/16/2002
• Est. Priority Date: 12/17/1998
• Status: Expired due to Term

• Current Assignee: Rhodes Pharmaceuticals LP (Purdue Pharma L.P.)
• Original Assignee: Euroceltique SA
• Inventors: Krishnamurthy, Thinnayam N., Darke, Andrew
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): TRAN, SUSAN T
• Application Number:
  US09/465,159
• Time in Patent Office: 943 Days
• Field of Search: 424/461, 424/464, 424/484, 424/489, 424/490, 424/494, 424/468, 424/469
• US Class Current: 424/490
• CPC Class Codes: A61K 31/4458 only substituted in position 2, e.g. methylphenidate
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/167 with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface with further drug-free outer coating A61K9/5073
• CPC Class Codes: A61K 9/2081 with microcapsules or coated microparticles according to A61K9/50
• CPC Class Codes: A61K 9/2086 Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat active cores with a complete drug-free outer coat A61K9/28
• CPC Class Codes: A61K 9/209 containing drug in at least two layers or in the core and in at least one outer layer
• CPC Class Codes: A61K 9/2846 Poly(meth)acrylates
• CPC Class Codes: A61K 9/2893 Tablet coating processes mechanical aspects A61J3/06
• CPC Class Codes: A61K 9/5026 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/5047 Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/5073 having two or more different coatings optionally including drug-containing subcoatings
• CPC Class Codes: A61K 9/5078 with drug-free core
• CPC Class Codes: A61K 9/5084 Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs tablets containing such a mixture A61K9/2077
• CPC Class Codes: A61K 9/5089 Processes
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia

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.

Claims

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 substrates comprising a portion of the effective dose of a drug in immediate release form,

a hydrophobic material coated onto the surface of said substrates in an amount sufficient to retard the release of said drug,

an enteric coating applied over said hydrophobic coating in an amount sufficient to substantially delay the release of said drug from said substrate until after said formulation passes through the stomach,

the formulation further comprising the remaining portion of said drug in immediate release form;

wherein the oral dosage form provides a time to maximum plasma concentration at about 0.5 to about 4 hours after oral administration and wherein the duration of effect provided by the drug contained in the formulation falls below effective plasma concentrations at about 8 to about 12 hours after oral administration.

2. The formulation of claim 1, wherein said remaining portion of said drug is applied to said substrates over said enteric coating.

3. The formulation of claim 1, wherein a unit dose of said plurality of substrates are contained within a gelatin capsule, and said remaining portion of said drug is also contained within said 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 said enteric coated substrates.

4. The formulation of claim 1, wherein said hydrophobic material comprises a plasticized aqueous dispersion of an acrylic polymer which is sprayed onto the surface of said substrates.

5. The formulation of claim 4, wherein said substrates are subjected to oven curing at a temperature above the glass transition temperature of the plasticized acrylic polymer at a temperature from about 40 to about 50°

C. for a time period of at least about 12 hours prior to the application of said enteric coating.

6. The formulation of claim 1, which provides a peak plasma concentration of the drug which is from about 1.0 to about 2.0 times the plasma concentration of the drug provided by the formulation at about 9 hours after oral administration.

7. The formulation of claim 1, wherein the oral dosage form provides a time to maximum plasma concentration at about 0.5 to about 2 hours after oral administration.

8. The formulation of claim 6, wherein the peak plasma concentration is from about 1.0 to about 1.7 times the plasma concentration of drug provided by the formulation at about 9 hours after oral administration.

9. The formulation of claim 6, wherein the duration of effect provided by the drug contained in the oral dosage form 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:

12. A method for preparing 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

preparing a plurality of substrates comprising a portion of the effective dose of a drug in immediate release form by spraying a solution of the drug onto said substrates;

applying a hydrophobic material to said substrates in an amount to retard the release of said drug;

applying an enteric coating over said hydrophobic coating in an amount sufficient to substantially delay the release of said drug from said substrate until after said formulation passes through the stomach;

applying an immediate release overcoat of said drug onto said enteric coated substrates;

wherein the oral dosage form provides a time to maximum plasma concentration at about 0.5 to about 4 hours after oral administration and wherein the duration of effect provided by the drug contained in the formulation falls below effective plasma concentrations at about 8 to about 12 hours after oral administration.

13. The method of claim 12, wherein the hydrophobic material is derived from an aqueous dispersion of plasticized acrylic polymer, said hydrophobic material being subjected to oven curing at a temperature above the glass transition temperature of the plasticized acrylic polymer at a temperature from about 40 to about 50°

C. for a time period of about 12 to about 24 hours, prior to the application of said enteric coating.

14. The method claim 12, wherein said enteric coating is derived from a solution of acrylic/methacrylic copolymers dispersion, triethyl citrate and talc.

15. The method of claim 12, wherein formulation provides an in-vitro dissolution as follows:

16. The method of claim 15, wherein said formulation provides a time to maximum plasma concentration of the drug at about 0.5 to about 4 hours after oral administration and a peak plasma concentration of the drug which is from about 1.0 to about 2.0 times the plasma concentration of the drug provided by the formulation at about 9 hours after oral administration.

17. The method of claim 15, wherein the plasma concentration of the drug when administered to a human patient falls below effective plasma concentrations at about 8 to about 12 hours after oral administration.

18. The method of claim 17, wherein the formulation provides a time to maximum plasma concentration at about 0.5 to about 2 hours after oral administration.