Taste-masked pharmaceutical compositions with gastrosoluble pore-formers

• US 10,471,017 B2
• Filed: 12/21/2016
• Issued: 11/12/2019
• Est. Priority Date: 10/21/2004
• Status: Active Grant

• Current Assignee: Adare Pharmaceuticals, Inc.
• Original Assignee: Adare Pharmaceuticals, Inc.
• Inventors: Lai, Jin-Wang, Venkatesh, Gopi M., Qian, Ken Kangyi
• Primary Examiner(s): Bredefeld, Rachael E
• Application Number:
  US15/387,317
• Publication Number:
  US 20170105942A1
• Time in Patent Office: 1,056 Days
• Field of Search: 424470
• CPC Class Codes: A61K 31/135 having aromatic rings , e.g. ketamine, nortriptyline methadone A61K31/137
• CPC Class Codes: A61K 31/4045 Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
• CPC Class Codes: A61K 31/495 having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazinesA61K31/48 takes precedence ; with three nitrogen atoms A61K31/53
• 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 9/2081 with microcapsules or coated microparticles according to A61K9/50
• CPC Class Codes: A61K 9/501 Inorganic compounds
• 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 9/5078 with drug-free core

Abstract

There is provided a method for preparing an orally disintegrating tablet (ODT) composition comprising microparticles of one or more task-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 forming a smooth, easy-to-swallow suspension. Furthermore, the microparticles (crystals, granules, beads or pellets containing the active), coated with a taste-masking membrane comprising a water-insoluble polymer and one or more gastrosoluble inorganic or organic pore-formers (practically insoluble in water and saliva, but soluble in an acidic buffer), exhibit acceptable taste-masking when placed in the oral cavity and provide rapid, substantially-complete release of the dose on entry into the stomach.

Claims

1. A pharmaceutical composition comprising:

(1) a plurality of taste-masked particles, wherein each taste-masked particle comprises;

(a) a drug-containing core particle;

(b) a taste-masking membrane disposed on said drug-containing core particle comprising a combination of (i) a water-insoluble polymer and (ii) a gastrosoluble inorganic or organic pore-former at a ratio ranging from about 85/15 to about 65/35, wherein the water-insoluble polymer is selected from the group consisting of ethyl cellulose, polyvinyl acetate, cellulose acetate, cellulose acetate phthalate, cellulose acetate butyrate, methacrylate copolymers and combinations thereof, and the gastrosoluble organic or inorganic pore-former is selected from the group consisting of calcium carbonate, calcium phosphate, calcium saccharide, calcium succinate, calcium tartrate, ferric acetate, ferric hydroxide, ferric phosphate, magnesium carbonate, magnesium citrate, magnesium hydroxide, magnesium oxide, magnesium phosphate and mixtures thereof, and the composition releases greater than or equal to about 60% of the total amount of drug in 30 minutes when tested for dissolution using United States Pharmacopoeia Apparatus 2 using paddles at 50 rpm in 900 mL of pH 1.2 buffer; and

(2) a plurality of rapidly-dispersing microgranules having an average particle size of not more than about 400 μ

m comprising (i) a disintegrant and (ii) a sugar alcohol or a saccharide or a combination thereof, wherein each of said disintegrant and sugar alcohol or saccharide is present in the form of particles having an average particle diameter of not more than about 30 μ

m, wherein the ratio of said sugar alcohol, said saccharide or combination thereof to said disintegrant in the rapidly-dispersing microgranules is from about 90/10 to about 99/1;

wherein the pharmaceutical composition is an orally disintegrating tablet.

2. The pharmaceutical composition of claim 1, wherein said taste-masked particles release less than or equal to about 10% of the total amount of drug in about 3 minutes when dissolution tested in simulated saliva fluid at about pH 6.8.

3. The pharmaceutical composition of claim 1, comprising one or more drug(s) present in a therapeutically effective amount.

4. The pharmaceutical composition of claim 1, wherein the drug is selected from the group consisting of diphenhydramine, ranitidine, famotidine, cetirizine, fexofenadine, sumatriptan, eletriptan, zolmitriptan, ondansetron, granisetron, tiagabine, tizanidine, zolpidem, zaleplon, zafirlukast, montelukast, sildenafil, tadalafil, pharmaceutically acceptable salts thereof, and combinations thereof.

5. The pharmaceutical composition of claim 1, wherein the drug-containing particle comprises a drug-layered bead comprising an inert particle coated with one or more pharmaceutically acceptable drug(s).

6. The pharmaceutical composition of claim 1, wherein the drug-containing particle comprises a microgranule or an extruded and/spheronized pellet comprising:

1) one or more pharmaceutically acceptable drug(s),

     2) a polymeric binder, and

     3) a filler and/or diluent.

7. The pharmaceutical composition of claim 1, wherein said drug requires taste-masking.

8. The pharmaceutical composition of claim 1, wherein the membrane thickness ranges from about 5% to 50% by weight of the coated particle.

9. The pharmaceutical composition of claim 1, wherein the water-insoluble polymer comprises ethylcellulose and the gastrosoluble pore former comprises calcium carbonate.

10. The pharmaceutical composition of claim 1, wherein the ratio of rapidly-dispersing microgranules to taste-masked particles ranges from about 6/1 to about 2/1.

11. The pharmaceutical composition of claim 1, wherein the rapidly-dispersing microgranules comprise a disintegrant selected from the group consisting of crosslinked polyvinylpyrrolidone, sodium starch glycolate, crosslinked sodium carboxymethylcellulose, low-substituted hydroxypropylcellulose and mixtures thereof.

12. The pharmaceutical composition of claim 1, wherein the average particle size of the drug-containing core particle is less than or equal to about 400 μ

m.

13. The pharmaceutical composition of claim 1, wherein said orally disintegrating tablet has a friability of less than or equal to about 1%.

14. The pharmaceutical composition of claim 1, wherein said orally disintegrating tablet disintegrates on contact with saliva in an oral cavity within approximately 60 seconds.

15. The pharmaceutical composition of claim 1, wherein the rapidly dispersing microgranules comprise a sugar alcohol or a saccharide selected from the group consisting of mannitol, xylitol, sorbitol, maltol, maltitol, lactose, sucrose, maltose, and combinations thereof.

16. The pharmaceutical composition of claim 1, wherein the gastrosoluble organic or inorganic pore former is a salt.

17. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition exhibits acceptable taste-masking when placed in the oral cavity for 60 seconds.

18. The pharmaceutical composition of claim 1, wherein the rapidly dispersing microgranules have an average particle size of less than or equal to about 300 μ

m.

19. A method of manufacturing a pharmaceutical composition comprising:

(a) preparing core particles comprising a drug;

(b) coating the core particles by applying a membrane comprising a mixture of (i) water-insoluble polymer and (ii) a gastrosoluble organic or inorganic pore former present at a ratio of from about 85/15 to about 65/35 wherein the water-insoluble polymer is selected from the group consisting of ethyl cellulose, polyvinyl acetate, cellulose acetate, cellulose acetate phthalate, cellulose acetate butyrate, methacrylate copolymers and combinations thereof, and the gastrosoluble organic or inorganic pore-former is selected from the group consisting of calcium carbonate, calcium phosphate, calcium saccharide, calcium succinate, calcium tartrate, ferric acetate, ferric hydroxide, ferric phosphate, magnesium carbonate, magnesium citrate, magnesium hydroxide, magnesium oxide, magnesium phosphate and mixtures thereof;

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

m, with a disintegrant having an average particle diameter of not more than 30 μ

m to produce rapidly-dispersing microgranules with an average particle size of not more than about 400 μ

m, wherein the ratio of said sugar alcohol, said saccharide or combination thereof to said disintegrant in the rapidly-dispersing microgranules is from about 90/10 to about 99/1;

(d) blending the membrane coated particles of step (b) with the rapidly-dispersing microgranules of step (c) at a ratio of about 1/6 to about 1/2; and

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

20. The method of claim 19, wherein the water-insoluble polymer comprises ethyl cellulose and the gastrosoluble organic or inorganic pore former comprises calcium carbonate.

21. The method of claim 19, wherein said step of compressing (e) comprises utilizing a conventional rotary tablet press equipped with an external lubrication system to pre-lubricate the dies and punches.

22. The method of claim 19, wherein the orally disintegrating tablets, when tested for dissolution using United States Pharmacopoeia Apparatus 2 using paddles at 50 rpm in 900 mL buffer, release less than or equal to about 10% of the total amount of the drug in about 3 minutes in a simulated saliva buffer at pH 6.8 and greater than or equal to about 60% of the total amount of the drug in about 30 minutes in an acidic buffer at pH 1.2.

23. The method of claim 19, wherein said rapidly-dispersing microgranules have an average particle size of not more than 300 μ

m.

24. The method of claim 19, wherein the membrane is present in an amount of from about 5% to about 50% based on the total weight of the coated particles.

25. The method of claim 19, wherein the pharmaceutical composition exhibits acceptable taste-masking when the composition is placed in the oral cavity for 60 seconds.

26. The method of claim 19, wherein the pharmaceutical composition releases greater than or equal to about 60% of the total amount of the drug in 30 minutes when tested for dissolution using United States Pharmacopeia Apparatus 2 using paddles at 50 rpm in 900 mL of pH 1.2 buffer.