Orally disintegrating tablets of atomoxetine

• US 20060057199A1
• Filed: 09/09/2005
• Published: 03/16/2006
• Est. Priority Date: 09/13/2004
• Status: Active Grant

• Current Assignee: Adare Pharmaceuticals, Inc.
• Original Assignee: Aptalis Pharmatech Incorporated
• Inventors: Venkatesh, Gopi M., Taylor, John, Harmon, Troy M.
• Granted Patent: US 8,747,895 B2
• Time in Patent Office: Days
• US Class Current: 424/469
• CPC Class Codes: A61K 8/0241 Containing particulates characterized by their shape and/or structure see also A61K8/04, A61K8/11, and A61K8/14, further aspects are classified in A61K2800/40 and subcodes
• 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 9/2077 Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
• CPC Class Codes: A61K 9/5078 with drug-free core

Abstract

A coated multi-particulate pharmaceutical dosage form such as an orally disintegrating tablet (ODT) presentation for delivering atomoxetine or a pharmaceutically acceptable salt thereof, a selective norepinephrine reuptake inhibitor indicated for the treatment of ADHD, into the body to maintain a therapeutically effective amount of atomoxetine in the plasm. The dosage form may comprise one or more populations of coated atomoxetine-containing particles (beads, pellets, granules etc.) providing a pre-designed rapid release profile after a predesigned lag-time of about 0 to 6 hours following oral administration.

Claims

1. A multiparticulate pharmaceutical dosage form comprising:

(a) timed, pulsatile-release (TPR) beads wherein the TPR beads comprise immediate release (IR) beads comprising atomoxetine or a pharmaceutically acceptable salt thereof coated with a TPR membrane comprising a combination of a water-insoluble polymer and an enteric polymer wherein said TPR membrane provides release of the drug after a lag time of about 1-6 hours following oral administration.

2. The dosage form of claim 1 further comprising:

(b) rapidly-dispersing microgranules comprising a disintegrant and a sugar alcohol or a saccharide or a combination thereof, the sugar alcohol or saccharide having an average particle diameter of not more than about 30 μ

m.

3. The dosage form of claim 1 further comprising taste-masked beads comprising IR beads coated with a taste-masking membrane, wherein said IR beads contain atomoxetine or a pharmaceutically acceptable salt thereof and said taste-masking membrane comprises a water-insoluble polymer.

4. The dosage form of claim 3 wherein said taste-masked beads and TPR beads comprising atomoxetine or a pharmaceutically acceptable salt thereof are present in said dosage form at a ratio of taste-masked beads to TPR beads of from about 30:

70 to about 90;

10 by weight.

5. The dosage form of claim 2 wherein the ratio of rapidly-dispersing microgranules to TPR beads alone or in combination with taste-masked beads is within the range of from about 9:

1 to 2;

1 by weight.

6. The dosage form of claim 5 wherein said dosage form disintegrates on contact with the saliva in the buccal cavity within about 60 seconds forming a smooth easy-to-swallow suspension.

7. The dosage form as defined in claim 1 wherein said water insoluble polymer is selected from the group consisting of ethylcellulose, cellulose acetate, cellulose acetate butyrate, polyvinyl acetate, neutral methacrylate acid copolymers and mixtures thereof and said enteric polymer is selected from the group consisting of cellulose acetate phthalate, cellulose acetate succinate, polyvinyl acetate phthalate, hypromellose phthalate, anionic methacrylic acid copolymers and mixtures thereof.

8. The dosage form as defined in claim 3 wherein said taste-masking membrane comprises a water-insoluble ethylcellulose or polyvinyl acetate and the membrane is present in an amount of about 5% to about 40% based on the total weight of the coated bead.

9. The dosage form as defined in claim 1 wherein said TPR membrane comprises a water-insoluble polymer and an enteric polymer at a weight ratio of from about 10:

1 to about 1;

1.

10. The dosage form of claim 9 wherein said TPR membrane is present in an amount of about 10% to about 60% based on the total weight of the coated TPR bead.

11. The dosage form of claim 10 wherein said TPR membrane further comprises a plasticizer selected from the group consisting of triacetin, tributyl citrate, tri-ethyl citrate, acetyl tri-n-butyl citrate, diethyl phthalate, dibutyl sebacate, polyethylene glycol, polypropylene glycol, castor oil and acetylated mono- and di-glycerides and mixtures thereof.

12. The dosage form of claim 1 wherein said IR bead comprises an inert particle coated with atomoxetine or a pharmaceutically acceptable salt thereof in a polymeric binder selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone and mixtures thereof.

13. The dosage form of claim 12 wherein said inert particle is selected from the group consisting of sugar spheres, cellulose spheres, and silicone dioxide spheroids.

14. The dosage form of claim 2 wherein said disintegrant is selected from the group consisting of crosslinked polyvinyl pyrrolidone, crosslinked sodium carboxymethylcellulose, sodium starch glycolate, low-substituted hydroxypropylcellulose and mixtures thereof.

15. The dosage form of claim 2 wherein said sugar alcohol or saccharide is selected from the group consisting of mannitol, xylitol, sorbitol, maltol, lactose, sucrose and mixtures thereof.

16. The dosage form of claim 3 wherein said taste-masked beads release substantially all of the atomoxetine contained in said beads within about 2 hours following oral administration.

17. The dosage form as defined in claim 16 wherein said TPR beads release substantially all of the atomoxetine contained in said TPR beads within about 4 hours following a predetermined lag-time of approximately 1 to 6 hours following oral administration.

18. The dosage form as defined in claim 1 wherein said dosage form contains a total of from about 10 mg to 60 mg of atomoxetine.

24. A method for treating a patient which comprises administering to the patient the dosage form of claim 1.

25. The method of claim 24 wherein said patient is a child or adolescent being treated for ADHD.

19. A method for the preparation of multi-particulate pharmaceutical dosage form comprising the steps of:

(a) preparing rapidly-dispersing microgranules by granulating a powder mixture comprising a sugar alcohol or a saccharide or a combination thereof having an average particle diameter of not more than about 30 μ

m and a disintegrant,

(b) preparing TPR beads by applying to immediate release (IR) beads containing atomoxetine or a pharmaceutically acceptable salt thereof, a TPR coating comprising a combination of a water-insoluble polymer and an enteric polymer to achieve an in-vitro lag-time of about 1 to 6 hours,

(c) optionally, preparing taste-masked beads by coating IR beads with a water-insoluble polymer to impart taste-masking properties on IR beads,

(d) blending rapidly dispersing microgranules from step (a), TPR beads from step (b) and optionally taste-masked beads from step (c) at a ratio of about 70/30 to 100/0 (TPR beads to taste-masked beads), and

(e) compressing the blend from step (d) to form a tablet which rapidly disintegrates in the oral cavity.

20. The method of claim 19 wherein IR beads are prepared by layering atomoxetine or a pharmaceutically acceptable salt thereof from a polymeric binder solution on inert particles selected from the group consisting of sugar spheres, cellulose spheres, and silicon dioxide spheroids.

21. The method of claim 19 wherein said TPR coating comprises ethylcellulose (EC) in combination with hypromellose phthalate (HPMCP).

22. The method of claim 21 wherein EC and HPMCP are present at a weight ratio of from about 10:

1 to about 1;

1.

23. The method of claim 22 wherein said TPR beads are prepared by applying a TPR coating in an amount of from about 10% to about 60% based on the total weight of the coated TPR bead.