Compositions for treatment of attention deficit hyperactivity disorder

• US 9,023,389 B1
• Filed: 01/05/2015
• Issued: 05/05/2015
• Est. Priority Date: 03/23/2011
• Status: Active Grant

• Current Assignee: Formulation Technologies, LLC (Akela Pharma, Inc.), 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:
  US14/589,839
• Publication Number:
  US 20150125521A1
• Time in Patent Office: 120 Days
• Field of Search: None
• US Class Current: 424/461
• 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 9/4808 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 9/5026 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 9/5084 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: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/26 Psychostimulants, e.g. nicotine, cocaine

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 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 the formulation provides an 8 hour lag time during which the formulation releases no more than 10% of the total methylphenidate or a pharmaceutical salt thereof followed by a sustained release period of 10-12 hours when the composition is placed in 700 ml aqueous solution of 0.1N HCl pH 1.1, for up to 2 hours followed by 2-6 hours in sodium phosphate buffer at pH 6.0;

followed by 6-20 hours in sodium phosphate buffer, pH 7.2 at 37°

C.±

0.5°

C., as measured by the USP Apparatus I.

2. The solid, oral pharmaceutical composition of claim 1, wherein the formulation releases between 0 and about 5% of the drug after 8 hours, between about 5% and about 30% after 10 hours, between about 20% and about 65% after 12 hours and between 45% and 95% after 15 hours, and wherein the rate of release between about 8 and about 12 hours is lower than the rate of release from about 12 to about 16 hours when the composition is placed in 700 ml aqueous solution of 0.1N HCl pH 1.1, for 2 hours followed by hours 2-6 in sodium phosphate buffer at pH 6.0;

followed by hours 6-20 in sodium phosphate buffer, pH 7.2 at 37°

C.±

0.5°

C., as measured by the USP Apparatus I.

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

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

5. 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.

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

7. 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 and at least one pharmaceutically acceptable excipient.

8. 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.

9. 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.

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

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

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

13. 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.

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

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

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

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

18. 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.

19. The solid, oral pharmaceutical composition of claim 1, further comprising an abuse deterrent agent.

20. The solid, oral pharmaceutical composition of claim 1, further comprising a nasal irritant.

21. The solid, oral pharmaceutical composition of claim 20, wherein the nasal irritant is a capsaicinoid or sodium lauryl sulfate.

22. The solid, oral pharmaceutical composition claim 1, wherein the solid oral pharmaceutical composition is a particulate bead.

23. A solid, oral pharmaceutical composition, comprising a plurality of said particulate beads of claim 22 contained in a water soluble capsule.

24. The solid, oral pharmaceutical composition of claim 23, comprising 1 mg to 150 mg methylphenidate or a pharmaceutical salt thereof.

25. The solid, oral pharmaceutical composition of claim 1, wherein when a unit dose of the composition is orally administered to a human subject, plasma area under the curve at 6 hours (AUC_0-6) after administration is less than about 5% of total plasma area under the curve at 48 hours after administration (AUC_0-48).

26. The solid, oral pharmaceutical composition of claim 1, wherein when a unit dose of the composition is orally administered to a human, there is a lag period of at least 5 hours during which the plasma concentration of methylphenidate or a pharmaceutical salt thereof is less than 10% of the maximum concentration (C_max), wherein the plasma area under the curve at 10 hours (AUC_0-10) after administration is less than about 7% of AUC_0-48, and wherein the time to C_max (T_max) is between 12 and 19 hours after administration.