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

• US 9,066,869 B2
• Filed: 10/09/2013
• Issued: 06/30/2015
• Est. Priority Date: 12/17/1998
• Status: Expired due to Fees

• Current Assignee: Rhodes Pharmaceuticals LP (Purdue Pharma L.P.)
• Original Assignee: Purdue Pharma L.P.
• Inventors: Krishnamurthy, Thinnayam N., Darke, Andrew
• Primary Examiner(s): TRAN, SUSAN T
• Application Number:
  US14/049,677
• Publication Number:
  US 20140099361A1
• Time in Patent Office: 629 Days
• Field of Search: None
• US Class Current: 1/1
• 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 comprising a plurality of multi-layer release beads collectively comprising a dose of methylphenidate, each bead comprising:

(i) an outer immediate release layer comprising a portion of the dose of methylphenidate,

(ii) a release delaying layer under the outer immediate release layer, the release delaying layer comprising a pH-dependent polymer,

(iii) a controlled release layer under the release delaying layer, the controlled release layer comprising a hydrophobic material selected from the group consisting of an alkylcellulose, an acrylic polymer and mixtures thereof; and

(iv) an immediate release core under the controlled release layer, the immediate release core comprising a further portion of the dose of methylphenidate,

wherein from about 30% to about 40% of the dose of methylphenidate is in the outer immediate release layers of the beads and from about 60% to about 70% of the dose of methylphenidate is in the immediate release cores of the beads, and

the formulation provides

(a) a time to a maximum plasma concentration of methylphenidate at about 0.5 to about 4 hours after oral administration to a human patient,

(b) a plasma concentration of methylphenidate which does not differ by more than 10% during a measuring interval, wherein the measuring interval is from about 6 hours to about 12 hours, and

(c) an in-vitro dissolution as follows;

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

3. The formulation of claim 1, wherein about 40% of the dose of methylphenidate is in the outer immediate release layers of the beads and about 60% of the dose of methylphenidate is in the immediate release cores of the beads.

4. The formulation of claim 1, wherein about 30% of the dose of methylphenidate is in the outer immediate release layers of the beads and about 70% of the dose of methylphenidate is in the immediate release cores of the beads.

5. The formulation of claim 1, wherein the plurality of the multi-layer release beads is incorporated into a hard gelatin capsule.

6. The formulation of claim 1, wherein the immediate release core further comprises a spheroid or a bead.

7. The formulation of claim 6, wherein the spheroid or the bead is sprayed with the further portion of the dose of the methylphenidate.

8. The formulation of claim 1, wherein each bead comprises a coat of a barrier agent between the immediate release core and the controlled release layer.

9. The formulation of claim 8, wherein the barrier agent is hydroxypropylmethylcellulose.

10. The formulation of claim 1, wherein the dose is 20 mg.

20. A method of treating Attention Deficit Hyperactivity Disorder in a child comprising:

administering to the child once-a-day in the morning a formulation according to claim 1.

11. An oral controlled release formulation comprising a plurality of multi-layer release beads collectively comprising a dose of methylphenidate, each bead comprising:

(i) an outer immediate release layer comprising a portion of the dose of methylphenidate,

(ii) a release delaying layer under the outer immediate release layer, the release delaying layer comprising a pH-dependent polymer,

(iii) a controlled release layer under the release delaying layer, the controlled release layer comprising a hydrophobic material selected from the group consisting of an alkylcellulose, an acrylic polymer and mixtures thereof; and

(iv) an immediate release core under the controlled release layer, the immediate release core comprising a further portion of the dose of methylphenidate,

wherein from about 30% to about 40% of the dose of methylphenidate is in the outer immediate release layers of the beads and from about 60% to about 70% of the dose of methylphenidate is in the immediate release cores of the beads, and

the formulation provides

(a) a time to a maximum plasma concentration of methylphenidate at about 0.5 to about 2 hours after oral administration to a human patient,

(b) a plasma concentration of methylphenidate which does not differ by more than 10% during a measuring interval, wherein the measuring interval is from about 2 hours to about 6 hours, and

(c) an in-vitro dissolution as follows;

12. The formulation of claim 11, wherein the immediate release core further comprises a spheroid or a bead.

13. The formulation of claim 12, wherein the spheroid or the bead is sprayed with the further portion of the dose of the methylphenidate.

14. The formulation of claim 12, wherein each bead comprises a coat of a barrier agent between the immediate release core and the controlled release layer.

15. The formulation of claim 11, which provides effective plasma levels of methylphenidate for from about 8 to about 10 hours.

16. An oral controlled release formulation comprising a plurality of multi-layer release beads collectively comprising a dose of methylphenidate, each bead comprising:

(i) an outer immediate release layer comprising a portion of the dose of methylphenidate,

(ii) a release delaying layer under the outer immediate release layer, the release delaying layer comprising a pH-dependent polymer,

(iii) a controlled release layer under the release delaying layer, the controlled release layer comprising a hydrophobic material selected from the group consisting of an alkylcellulose, an acrylic polymer and mixtures thereof; and

(iv) an immediate release core under the controlled release layer, the immediate release core comprising a further portion of the dose of methylphenidate,

wherein from about 30% to about 40% of the dose of methylphenidate is in the outer immediate release layers of the beads and from about 60% to about 70% of the dose of methylphenidate is in the immediate release cores of the beads, and

the formulation provides

(a) a time to a maximum plasma concentration of methylphenidate at about 0.5 to about 2 hours after oral administration to a human patient,

(b) effective plasma levels of methylphenidate for from about 8 to about 10 hours, and

(c) an in-vitro dissolution as follows;

17. The formulation of claim 16, wherein the immediate release core further comprises a spheroid or a bead.

18. The formulation of claim 17, wherein the spheroid or the bead is sprayed with the further portion of the dose of the methylphenidate.

19. The formulation of claim 16, wherein each bead comprises a coat of a barrier agent between the immediate release core and the controlled release layer.