Multilayer orally disintegrating tablet

• US 8,603,525 B2
• Filed: 07/31/2007
• Issued: 12/10/2013
• Est. Priority Date: 08/04/2006
• Status: Active Grant

• Current Assignee: ETHYPHARM
• Original Assignee: ETHYPHARM
• Inventors: Oury, Pascal, Herry, Catherine, Hoarau, Didier
• Primary Examiner(s): Wax, Robert A
• Assistant Examiner(s): Palenik, Jeffrey T
• Application Number:
  US12/376,065
• Publication Number:
  US 20090311320A1
• Time in Patent Office: 2,324 Days
• Field of Search: None
• US Class Current: 424/472
• CPC Class Codes: A61K 31/167 having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• CPC Class Codes: A61K 31/4355 the heterocyclic ring system containing a five-membered ring having oxygen as a ring hetero atom
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• 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 9/2086 Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat active cores with a complete drug-free outer coat A61K9/28
• CPC Class Codes: A61K 9/2095 Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing mechanical aspects A61J3/00
• CPC Class Codes: A61K 9/5078 with drug-free core
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents

Abstract

An orally disintegrating multilayer tablet comprising at least two discrete layers, one of which comprises at least one active agent that promotes the oxidation of opioids, preferably acetaminophen, and the other of which contains granules including an inert core which is coated with at least one opioid and at least one binder, wherein said opioid coating is coated with a subcoat comprising a compound soluble in gastric fluids, said subcoat being coated with a taste-masking coating comprising a polymer or copolymer comprising dialkylaminoalkyl(meth)acrylate units and a pore-forming agent.

Claims

1. Orally disintegrating multilayer tablet comprising at least two discrete layers, one layer of which comprises at least one active agent that promotes the oxidation of opioids and the other layer of which contains opioid granules, said opioid granules including an inert core which is coated with at least one opioid and at least one binder, wherein said opioid coating is coated with a subcoat comprising a compound soluble in gastric fluids, wherein the subcoat limits the degradation of the opioid, said subcoat being coated with a taste-masking coating comprising a dialkylaminoalkyl(meth)acrylate copolymer and a pore-forming agent selected from the group consisting of a hydrophilic polymer soluble in gastric fluids and a binder, said opioid coating and said subcoat being free of any dialkylaminoalkyl(meth)acrylate copolymer.

2. Orally disintegrating multilayer tablet according to claim 1, wherein the tablet comprises 2 or 3 layers.

3. Orally disintegrating multilayer tablet according to claim 2, wherein the tablet comprises three layers, wherein a layer containing only excipients is inserted between the two layers respectively comprising acetaminophen and the opioid.

4. Orally disintegrating multilayer tablet according to claim 1, wherein the opioid is oxycodone or a pharmaceutically acceptable salt thereof.

5. Orally disintegrating multilayer tablet according to claim 4, wherein the opioid is oxycodone hydrochloride.

6. Orally disintegrating multilayer tablet according to claim 5, wherein the tablet comprises from 1 mg to 20 mg oxycodone hydrochloride.

7. Orally disintegrating multilayer tablet according to claim 1, wherein the tablet comprises from 100 mg to 750 mg acetaminophen as the at least one active agent that promotes oxidation of opioids.

8. Orally disintegrating multilayer tablet according to claim 1, wherein the inert core is a sugar core.

9. Orally disintegrating multilayer tablet according to claim 1, wherein said binder is chosen from the group consisting of:

cellulose-based polymers;

acrylic polymers;

polyvinyl alcohols;

alginic acid or sodium alginate;

starch or pregelatinized starch;

sucroses and derivatives thereof;

guar gum;

polyethylene glycols; and

mixtures and copolymers thereof.

10. Orally disintegrating multilayer tablet according to claim 9, wherein the binder is hydroxypropylmethylcellulose, hydroxypropylcellulose or hydroxyethylcellulose.

11. Orally disintegrating tablet according to claim 1, wherein the compound soluble in gastric fluids is hydroxypropylmethylcellulose.

12. Orally disintegrating multilayer tablet according to claim 1, wherein the dialkylaminoalkyl(meth)acrylate copolymer is a copolymer of dimethylaminoethyl methacrylate, methylmethacrylate and n-butyl methacrylate.

13. Orally disintegrating multilayer tablet according to claim 1, wherein each layer comprises a mixture of excipients comprising:

at least one soluble agent, and

at least one disintegrating agent and/or at least one swelling agent.

14. Orally disintegrating multilayer tablet according to claim 13, wherein the disintegrating agent is crospovidone.

15. Orally disintegrating multilayer tablet according to claim 13, wherein said excipients in the opioid layer further comprise an anti-oxidant agent.

16. Orally disintegrating multilayer tablet according to claim 15, wherein said anti-oxidant agent is ascorbyl palmitate.

17. Method for preparing the tablet according to claim 1, comprising the following steps:

1. preparing optionally coated particles of an active agent that promotes the oxidation of opioids;

2. preparing granules comprising an opioid coating applied onto an inert core, the opioid coating comprising an opioid and at least one binder and being coated with a subcoat comprising a compound soluble in gastric fluids, said subcoat being coated with a taste-masking coating comprising a polymer, a copolymer comprising dialkylaminoalkyl (meth)acrylate units and a pore-forming agent;

3. preparing at least two dry mixtures each comprising tableting excipients, one of which contains said active agent particles and the other of which contains the above granules;

4. precompressing at least one of the dry mixtures obtained above;

5. applying another mixture to the above mixture;

6. optionally precompressing; and

finally compressing the preformed layers obtained above,

steps 5 and 6 possibly being repeated at least once depending on the number of layers of the tablet.

18. Method according to claim 17, wherein Step 2 comprises applying the opioid coating by spraying a suspension of the opioid in a hydroalcoholic medium onto the inert core.

19. Orally disintegrating multilayer tablet according to claim 1, wherein the at least one active agent that promotes the oxidation of opioids comprises acetaminophen.

20. Orally disintegrating multilayer tablet according to claim 1, wherein the pore-forming agent is hydroxypropylmethylcellulose.