Oral pharmaceutical dosage forms

• US 10,328,068 B2
• Filed: 12/22/2017
• Issued: 06/25/2019
• Est. Priority Date: 11/03/2008
• Status: Active Grant

• Current Assignee: Orient Pharma Company Limited
• Original Assignee: DURECT Corporation
• Inventors: Scicinski, Jan J., van Osdol, William W., Su, Huey-Ching, Arenberg, Michael H., Shah, Jaymin
• Primary Examiner(s): Sasan, Aradhana
• Application Number:
  US15/853,013
• Publication Number:
  US 20180214435A1
• Time in Patent Office: 550 Days
• Field of Search: None
• 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 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/1623 Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• 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 9/4858 Organic compounds
• 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

Abstract

Controlled release oral dosage forms suitable for administration of methylphenidate are provided. Abuse-resistant controlled release oral dosage forms suitable for administration of methylphenidate are also provided. Methods of treating ADD and ADHD using the oral dosage forms are also provided.

Claims

1. An oral controlled release dosage form comprising a formulation comprising:

methylphenidate;

sucrose acetate isobutyrate (SAIB);

isopropyl myristate (IPM);

cellulose acetate butyrate (CAB);

triacetin;

SiO₂; and

a saturated polyglycolized glyceride.

2. The oral controlled release dosage form of claim 1, wherein the methylphenidate is present in the formulation at about 5 to about 30 wt % relative to the total weight of the formulation.

3. The oral controlled release dosage form of claim 1, wherein the SAIB is present in the formulation at about 30 to about 45 wt % relative to the total weight of the formulation.

4. The oral controlled release dosage form of claim 1, wherein the IPM is present in the formulation at about 2 to about 15 wt % relative to the total weight of the formulation.

5. The oral controlled release dosage form of claim 1, wherein the CAB is present in the formulation at about 2 to about 10 wt % relative to the total weight of the formulation.

6. The oral controlled release dosage form of claim 1, wherein the triacetin is present in the formulation at about 15 to about 40 wt % relative to the total weight of the formulation.

7. The oral controlled release dosage form of claim 1, wherein the SiO₂ is present in the formulation at about 0.1 to about 2 wt % relative to the total weight of the formulation.

8. The oral controlled release dosage form of claim 1, wherein the saturated polyglycolized glyceride is present in the formulation at about 0.01 to about 5 wt % relative to the total weight of the formulation.

9. The oral controlled release dosage form of claim 1, wherein:

the methylphenidate is present in the formulation at about 5 to about 30 wt % relative to the total weight of the formulation;

the SAIB is present in the formulation at about 30 to about 45 wt % relative to the total weight of the formulation;

the IPM is present in the formulation at about 2 to about 15 wt % relative to the total weight of the formulation;

the CAB is present in the formulation at about 2 to about 10 wt % relative to the total weight of the formulation;

the triacetin is present in the formulation at about 15 to about 40 wt % relative to the total weight of the formulation;

the SiO₂ is present in the formulation at about 0.1 to about 2 wt % relative to the total weight of the formulation; and

the saturated polyglycolized glyceride is present in the formulation at about 0.01 to about 5 wt % relative to the total weight of the formulation.

10. The controlled release oral dosage form of claim 1, wherein said dosage form is characterized by providing:

(i) an initial increasing in vivo rate of release of methylphenidate from the controlled release dosage form suitable to provide an initial increasing-rate phase of less than or equal to about 2 hours, and sufficient to provide a therapeutically effective amount of methylphenidate for a rapid onset of action; and

(ii) a second, non-ascending in vivo rate of release of methylphenidate from the controlled release dosage form that provides a subsequent non-ascending phase sufficient to provide a therapeutically effective amount of methylphenidate through at least 11 hours post administration.

11. The controlled release oral dosage form of claim 10, wherein the initial increasing-rate phase is sufficient to provide an onset of action within about 1 hour post administration.

12. The controlled release oral dosage form of claim 10, wherein the subsequent non-ascending phase is sufficient to provide a therapeutically effective amount of methylphenidate through at least 12 hours post administration.

13. The controlled release oral dosage form of claim 1, wherein the dosage form is abuse-resistant.

14. The abuse-resistant controlled release oral dosage form of claim 13, wherein the formulation provides a decreased risk of misuse or abuse.

15. The abuse-resistant controlled release oral dosage form of claim 14, wherein said decreased risk of misuse or abuse is characterized by a low in vitro solvent extractability value of the methylphenidate from the dosage form, wherein less than 45% of the methylphenidate is extracted after 60 min of extraction in 40% ethanol at 25°

C.

16. The abuse-resistant controlled release oral dosage form of claim 14, wherein said decreased risk of misuse or abuse is characterized by a C_max ratio for methylphenidate when the dosage form is ingested by a subject with water relative to when the dosage form is ingested by the subject with 40% ethanol of about 0.8 to 1.2, and an AUC ratio for methylphenidate when the dosage form is ingested by the subject with water relative to when the dosage for is ingested by the subject with 40% ethanol of about 0.8 to 1.2.

17. The abuse-resistant controlled release oral dosage form of claim 14, wherein said decreased risk of misuse or abuse is characterized by a low injectability potential, wherein the force required to inject 1 gram of the formulation from a 3 ml syringe through an 18 G needle exceeds 62 N at a crosshead speed of 150 mm/min at 25°

C.

18. The abuse-resistant controlled release oral dosage form of claim 13, wherein said dosage form is not susceptible to common forms of abuse comprising injection, inhalation and volatilization.

19. A method of treating Attention Deficit Disorder (ADD) or Attention Deficit Hyperactivity Disorder (ADHD) in a subject, said method comprising administering the oral controlled release dosage form of claim 1 to the subject on a once-day (QD) basis.

20. A method of treating Attention Deficit Disorder (ADD) or Attention Deficit Hyperactivity Disorder (ADHD) in a subject, said method comprising administering the oral controlled release dosage form of claim 9 to the subject on a once-day (QD) basis.