Taste-masked pharmaceutical compositions

• US 20060078614A1
• Filed: 10/12/2005
• Published: 04/13/2006
• Est. Priority Date: 10/12/2004
• Status: Active Grant

• Current Assignee: Adare Pharmaceuticals, Inc.
• Original Assignee: Adare Pharmaceuticals, Inc.
• Inventors: Venkatesh, Gopi M.
• Granted Patent: US 9,884,014 B2
• Time in Patent Office: Days
• US Class Current: 424/469
• CPC Class Codes: A61K 9/0056 Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
• CPC Class Codes: A61K 9/2077 Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets

Abstract

There is provided a method for preparing an orally disintegrating tablet (ODT) composition comprising microparticles of one or more taste-masked active pharmaceutical ingredient(s), rapidly-dispersing microgranules, and other optional, pharmaceutically acceptable excipients wherein the ODT disintegrates on contact with saliva in the buccal cavity in about 60 seconds forming a smooth, easy-to-swallow suspension. Furthermore, the microparticles (crystals, granules, beads or pellets containing the active) applied with a taste-masking membrane comprising a combination of water-insoluble and gastrosoluble polymers release not less than about 60% of the dose is in the stomach in about 30 minutes, thus maximizing the probability of achieving bioequivalence to the reference IR product having rapid onset of action (short T_max). A process for preparing such compositions for oral administration using conventional fluid-bed equipment and rotary tablet press is also disclosed.

Claims

1. A pharmaceutical composition comprising a plurality of taste-masked particles, wherein the taste-masked particles comprise:

(a) a drug-containing core particle; and

(b) a taste-masking membrane on said drug-containing core particle comprising a combination of a water-insoluble polymer and a gastrosoluble polymer at a ratio ranging from about 95/5 to about 50/50 having a thickness of from about 5% to about 50% based on the weight of the coated particle and an average particle size of not more than about 400 μ

m wherein the composition exhibits acceptable taste-masking when the composition is placed in the oral cavity for 60 seconds and the composition releases not less than about 60% of the dose in 30 min when tested for dissolution using United States Pharmacopoeia Apparatus 2 (paddles@ 50 rpm in 900 mL of pH 1.2 buffer).

2. A pharmaceutical composition in accordance with claim 1 further comprising:

c) a plurality of rapidly-dispersing microgranules with an average particle size of not more than about 300 μ

m comprising (i) a disintegrant and (ii) a sugar alcohol or a saccharide or a combination thereof, each having an average particle diameter of not more than about 30 μ

m;

d) one or more pharmaceutically acceptable excipients,

wherein said composition as a tablet exhibits at least one of the following properties;

(1) exhibits a friability of not more than about 1% in order to be suitable for packaging in blisters and bottles for storage, transportation and commercial distribution, and

(2) disintegrates on contact with the saliva in the oral cavity within approximately 60 seconds.

3. The pharmaceutical composition of claim 2 in the form of an orally disintegrating tablet (ODT).

4. The pharmaceutical composition of claim 2 wherein said taste-masked microparticles release not more than about 10% in about 3 minutes when dissolution tested in a simulated saliva fluid (pH 6.8).

5. The pharmaceutical composition of claim 1 comprising one or more active pharmaceutical ingredient(s) in sufficient quantities to be administered orally to a patient at prescribed dosing regimen to provide therapeutic efficacy.

6. The pharmaceutical composition of claim 1 wherein said drug-containing core particle comprises a drug-layered bead comprising an inert particle coated with one or more pharmaceutically acceptable actives from a polymeric binder solution.

7. The pharmaceutical composition of claim 1 wherein the drug-containing particle comprises a microgranule or an extruded/spheronized pellet comprising one or more pharmaceutically acceptable active ingredient(s), a polymeric binder and a hydrophilic filler/diluent.

8. The pharmaceutical composition of claim 1 wherein said drug is a pharmaceutically acceptable active ingredient requiring taste-masking.

9. The pharmaceutical composition of claim 1 wherein the drug is selected from the group consisting of ranitidine, cimetidine, famotidine, astemizole, cetirizine, fexofenadine, omeprazole, lansoprazole, sumatriptan, rezitriptan, electriptan, zolmitriptan, ondansetron, granisetron, clonazepam, tiagabine, tizanidine, zolpidem, zaleplon, zafirlukast, montelukast, sildenafil, tadalafil and combinations thereof.

10. The pharmaceutical composition of claim 1 wherein the water-insoluble polymer and the gastrosoluble polymer are present at a weight ratio of from about 95/5 to 50/50 and the membrane thickness is from about 5% to 50% by weight.

11. The pharmaceutical composition of claim 1 wherein the water-insoluble polymer is selected from the group consisting of polyvinyl acetate, cellulose acetate, cellulose acetate butyrate, methacrylate copolymers and combinations thereof.

12. The pharmaceutical composition of claim 1 wherein the gastrosoluble polymer is selected from the group consisting of maltrin, aminoalkyl methacrylate copolymer, polyvinylacetate diethylaminoacetate, and combinations thereof.

13. The pharmaceutical composition of claim 1 wherein the water-insoluble polymer comprises ethylcellulose and the gastrosoluble polymer comprises an aminoalkyl methacrylate copolymer.

14. The pharmaceutical composition of claim 2 wherein the sugar alcohol and/or saccharide to disintegrant ratio is from about 90/10 to about 99/1.

15. The pharmaceutical composition of claim 2 wherein the rapidly-dispersing microgranules and taste-masked microparticles are present in a ratio of about 6/1 to 2/1.

16. The pharmaceutical composition of claim 3 wherein said rapidly-dispersing microgranules comprise a disintegrant selected from the group consisting of crosslinked polyvinylpyrrolidone, sodium starch glycolate, crosslinked carboxymethyl cellulose of sodium, low-substituted hydroxylpropylcellulose and mixtures thereof, and the sugar alcohol or saccharide is selected from the group consisting of mannitol, xylitol, sorbitol, maltol, maltitol lactose, sucrose, maltose and combinations thereof.

17. A method of manufacturing a pharmaceutical composition comprising:

a) preparing core particles comprising an active pharmaceutical ingredient; and

b) coating the core particles by applying a membrane comprising a mixture of water-insoluble polymer and a gastrosoluble polymer present at a ratio of from about 95/5 to about 50/50, the membrane coating comprising from about 5% to about 50% based on the total weight of the coated particles, wherein the composition exhibits the following properties;

1) acceptable taste-masking when the composition is placed in the oral cavity for 60 seconds; and

2) releases not less than about 60% of the active in 30 min when tested for dissolution using United States Pharmacopoeia Apparatus 2 (paddles @ 50 rpm in 900 mL of pH 1.2 buffer).

18. The method of claim 17 wherein the water-insoluble polymer is selected from the group consisting of ethylcellulose, polyvinyl acetate, cellulose acetate, cellulose acetate butyrate, methacrylate copolymers and combinations thereof.

19. The method of claim 17 wherein the gastroinsoluble polymer is selected from the group consisting of maltrin, aminoalkyl methacrylate copolymer, polyvinylacetate diethylaminoacetate, and combinations thereof.

20. The method of claim 17 wherein the water-insoluble polymer comprises ethylcellulose and the gastrosoluble polymer comprises an aminoalkyl methacrylate copolymer.

21. The method of claim 17 wherein the water-insoluble polymer and the gastrosoluble polymer are present at a weight ratio of from about 95/5 to 50/50 and the membrane thickness is from about 5% to 50% by weight.

22. The method of claim 17 further comprising:

c) granulating a sugar alcohol or a saccharide, or a combination thereof, each having an average particle diameter of not more than 30 μ

m, with a disintegrant to produce rapidly disintegrating microgranules with an average particle size not more than about 400 μ

m;

d) blending membrane coated microparticles of step (b) with rapidly disintegrating microgranules of step (c) at a ratio of about 1;

6 to about 1;

2; and

e) compressing the blend of step (d) into tablets.

23. The method of claim 22 wherein said step of compressing comprises utilizing a conventional rotary tablet press equipped with an external lubrication system to pre-lubricate the dies and punches.

24. The method of claim 22 wherein the tablet, when tested for dissolution using United States Pharmacopoeia Apparatus 2 (paddles @ 50 rpm in 900 mL buffer), releases not more than about 10% of the dose in about 3 minutes in a simulated saliva buffer at pH 6.8 and not less than about 60% of the dose in about 30 minutes in an acidic buffer at pH 1.2.

25. The method of claim 22 wherein said rapidly dispersing microgranules have an average particle size of not more than about 300 μ

m.