Compositions for treatment of attention deficit hyperactivity disorder

• US 9,283,214 B2
• Filed: 05/05/2015
• Issued: 03/15/2016
• Est. Priority Date: 03/23/2011
• Status: Active Grant

• Current Assignee: Ironshore Pharmaceuticals & Development, Inc.
• Original Assignee: Ironshore Pharmaceuticals & Development, Inc.
• Inventors: Lickrish, David, Zhang, Feng
• Primary Examiner(s): Krass, Frederick
• Assistant Examiner(s): Cohen, Michael P
• Application Number:
  US14/704,836
• Publication Number:
  US 20150231125A1
• Time in Patent Office: 315 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 31/4458 only substituted in position 2, e.g. methylphenidate
• CPC Class Codes: A61K 9/1676 having a drug-free core with discrete complete coating layer containing drug adsorbates of liquid drug formulations on inert powders without simultaneous granulation step A61K9/141; with further drug-free outer coating A61K9/5078; drug conjugated to non-active particles A61K47/6921
• CPC Class Codes: A61K 9/2072 characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms A61K9/0004, A61K9/0056, A61K9/0065 take precedence
• CPC Class Codes: A61K 9/2886 having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer of the type active core-drug layer-inactive layer A61K9/209
• CPC Class Codes: A61K 9/4808 characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release capsules filled with granules or microparticles A61K9/16; filled with microcapsules or coated microparticles A61K9/50; with mixture of different granules, microcapsules, (coated) microparticles A61K9/5084
• CPC Class Codes: A61K 9/4866 Organic macromolecular compounds
• CPC Class Codes: A61K 9/5015 Organic compounds, e.g. fats, sugars
• 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 9/5042 Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
• 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

Abstract

Therapeutic compositions and methods for treatment of attention deficit disorder (ADD) or attention deficit hyperactivity disorder (ADHD) include dosage forms that deliver a therapeutic amount of active drug in a delayed and controlled release formulation. The dosage form can be administered at night and drug release is delayed for from 4 to 6 hours or longer, followed by an ascending release rate.

Claims

1. A solid, oral pharmaceutical composition comprising:

a single population of beads, said beads comprising;

a core comprising methylphenidate or a pharmaceutical salt thereof and at least one pharmaceutically acceptable excipient;

a sustained release layer enclosing the core; and

a delayed release layer enclosing the sustained release layer, wherein when the formulation is administered to a human subject in a fasted state, (i) there is a lag of at least 7 hours during which the plasma concentration of methylphenidate is less than 5% of the maximum plasma (Cmax), (ii) a plasma area under the curve at 10 hours (AUC_0-10) after administration that is less than about 7% of AUC_0-48; and

(iii) wherein the time to C_max (T_max) is between 12 and 19 hours after administration, and wherein administration to a population of subjects provides a significant improvement in ADHD related behavior or cognitive ability over a period of at least 12 continuous hours as measured by a validated rating scale.

2. The solid, oral pharmaceutical composition of claim 1, wherein the core comprises a substantially spherical bead.

3. The solid, oral pharmaceutical composition of claim 1, wherein the core comprises methylphenidate hydrochloride.

4. The solid, oral pharmaceutical composition of claim 1, wherein the core comprises one or more excipients selected from polyvinyl pyrollidone, hydroxypropylmethyl cellulose, lactose, sucrose, microcrystalline cellulose and combinations of any thereof.

5. The solid, oral pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable excipient is microcrystalline cellulose.

6. The solid, oral pharmaceutical composition of claim 1, wherein the core comprises a nonpareil bead coated with a layer comprising the methylphenidate or a pharmaceutical salt thereof.

7. The solid, oral pharmaceutical composition of claim 1, wherein the delayed release layer comprises a pH dependent polymer or copolymer that is insoluble in aqueous medium at pH lower than 5.5.

8. The solid, oral pharmaceutical composition of claim 1, wherein the delayed release layer comprises cellulose acetate phthalate, cellulose acetate trimaletate, hydroxyl propyl methylcellulose phthalate, polyvinyl acetate phthalate, acrylic polymers, polyvinyl acetaldiethylamino acetate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate trimellitate, shellac, methacrylic acid copolymer or combinations of any thereof.

9. The solid, oral pharmaceutical composition of claim 1, wherein the sustained release layer comprises a plasticizer.

10. The solid, oral pharmaceutical composition of claim 9, wherein the plasticizer is dibutyl sebacate (DBS), tributyl citrate, acetyl tributyl citrate, acetyl triethyl citrate, mineral oil, castor oil or a fixed oil.

11. The solid, oral pharmaceutical composition of claim 9, wherein the delayed release layer comprises methacrylic acid copolymer Type B.

12. The solid, oral pharmaceutical composition of claim 9, wherein the delayed release layer comprises methacrylic acid copolymer Type B, mono- and diglycerides, dibutyl sebacate and polysorbate 80.

13. The solid, oral pharmaceutical composition of claim 1, wherein the sustained release layer comprises a water-insoluble and water-permeable polymer.

14. The solid, oral pharmaceutical composition of claim 13, wherein the sustained release layer further comprises a water soluble polymer.

15. The solid, oral pharmaceutical composition of claim 1, wherein the sustained release layer comprises ethyl cellulose, hydroxypropyl cellulose, dibutyl sebacate and a metal stearate.

16. The solid, oral pharmaceutical composition of claim 1, wherein the sustained release layer comprises ethyl cellulose, hydroxypropyl cellulose, dibutyl sebacate and magnesium stearate.

17. The solid, oral pharmaceutical composition of claim 1, wherein the delayed release layer comprises a cellulose ether derivative, an acrylic resin, a copolymer of acrylic acid and methacrylic acid esters with quaternary ammonium groups, a copolymer of acrylic acid and a methacrylic acid ester or a combination of any thereof.

18. The solid, oral pharmaceutical composition of claim 1, wherein said population of beads is contained in a water soluble capsule.

19. The solid, oral pharmaceutical composition of claim 18, comprising 1 mg to 150 mg of methylphenidate or a pharmaceutical salt thereof.

20. The solid, oral pharmaceutical composition of claim 18, comprising 80 mg of methylphenidate or a pharmaceutical salt thereof.

21. The composition of claim 1, wherein the improvement is measured by the ADHD-RS-IV scale, BSFQ, CGI, CGI-P, PREMB, Permanent Product Measure of Performance (PERMP) scores, or SKAMP rating scale.

22. The composition of claim 1, wherein when the formulation is administered to a population of adolescent or child subjects, the formulation provides a significant improvement in Permanent Product Measure of Performance scores over a period of at least about 12 continuous hours.

23. The composition of claim 22, wherein the formulation provides a significant improvement over placebo in Permanent Product Measure of Performance scores over a period from about 11 through about 23 hours post-dose.

24. The composition of claim 23, wherein when the formulation is administered at about 8-10 PM, the formulation provides a significant improvement in PERMP scores during a 10-12 hour period from about 7 AM to about 9 PM the following day.

25. The composition of claim 24, wherein the significant improvement is at least a 50% improvement over placebo.

26. The composition of claim 1, wherein when the formulation is administered to a population of adolescent or child subjects, the formulation provides a significant improvement in SKAMP scores during a period of about 12 continuous hours.

27. The composition of claim 26, wherein the formulation provides a significant improvement in SKAMP scores during a period from about 11 through about 23 hours post-dose.

28. The composition of claim 27, wherein when the formulation is administered at about 8-10 PM, the formulation provides a significant improvement in SKAMP scores during a 10-12 hour period from about 7 AM to about 9 PM the following day.

29. The composition of claim 1, wherein the formulation provides a measurable improvement in BSFQ scores over placebo when administered at about 8-10 PM.