DIVERSION-RESISTANT MICROGRANULES AND MICROTABLETS

• US 20130129825A1
• Filed: 06/07/2011
• Published: 05/23/2013
• Est. Priority Date: 06/07/2010
• Status: Active Grant

• Current Assignee: ETHYPHARM
• Original Assignee: ETHYPHARM
• Inventors: Billoet, Vincent
• Granted Patent: US 9,993,431 B2
• Time in Patent Office: Days
• US Class Current: 424/480
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 9/2009 Inorganic compounds
• CPC Class Codes: A61K 9/2022 Organic macromolecular compounds
• CPC Class Codes: A61K 9/2077 Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
• CPC Class Codes: A61K 9/4808 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 9/5078 with drug-free core
• 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 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Abstract

The invention relates to the use of an oral dosage form based on microgranules and/or microtablets to reduce the abusive use of at least one active principle contained therein. The aim of the invention is to prevent the diversion of an oral dosage form based on microgranules and/or microtablets containing at least one active principle capable of causing a dependency, a gelling agent, and a gelling activator. The gelling agent and the activator are only brought into contact with each other in the event of diversion by crushing. Said judiciously selected pair of excipients confers a viscosity to the formulation, such that said formulation cannot be administered by injection or does not release the active principle rapidly by forming a gel when it comes into contact with the mucous membrane if nasally administered.

Claims

1. Oral dosage form based on microgranules and/or microtablets comprising two populations of microgranules or microtablets, the first population comprising at least one active principle that could create a dependency and a gelling agent, and the second population, without active principle and gelling agent, comprising at least one gelling activator.

2. The dosage form according to claim 1, constituted of microgranules or microtablets.

3. The dosage form according to claim 2, further comprising a first population of microgranules comprising a neutral support and at feast one mounting layer comprising at least one active principle and optionally a pharmaceutically acceptable binder agent and a gelling agent present either in the mounting layer or in a separate layer, and a second population of microgranules comprising a neutral support and at least one mounting layer comprising at least one gelling activator.

4. The dosage form according to claim 1, wherein the gelling agents are chosen from polyacrylic acids and derivatives thereof, polyoxyethylenes, polyvinyl alcohols, polyvinylpyrrolidones (PVP), gelatines, derivatives of cellulose such as hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, polysaccharides, preferably in the sub-group comprising:

sodium alginate, pectins, guars, xanthans, carrageenans, gellans and mixtures thereof.

5. The dosage form according to claim 1, wherein the gelling activator, in association with the gelling agent, enables the formation of bridges at certain sites of the polymeric chains of the gelling agent or/and enables the reinforcement of the polymeric network of the gelling agent.

6. The dosage form according to claim 1, wherein, the gelling agent/gelling activator pair is chosen from carboxy polymethylene/sodium bicarbonate, alginate/Ca²⁺ ion, alginate/magnesium and aluminium silicates and xanthan gum/magnesium and aluminium silicates.

7. The dosage form according to claim 1, wherein the gelling agent is present in the dosage unit at a rate of 1 to 100 mg, more preferentially from 1 to 50 mg and even more preferentially from 1 to 30 mg.

8. The dosage form according to claim 1, wherein the gelling activator is present in the dosage unit at a rate of 1 to 100 mg, more preferentially from 1 to 50 mg and even more preferentially from 1 to 30 mg.

9. The dosage form according to claim 1, wherein the microgranules and/or the microtablets comprise a coating based on at least one hydrophobic polymer to prevent the immediate release of the active principle.

10. The dosage form according to claim 9, wherein the hydrophobic polymer is chosen from ethylcellulose, cellulose butyrate acetate, cellulose acetate, type A and type B ammonio-methacrylate copolymers sold under the trade name Eudragit®

, particularly Eudragit®

RS 30D, Eudragit NE 30D, Eudragit®

RL 30D, Eudragit®

RS PO and Eudragit®

RL PO of the family of poly(ethyl acrylate, methyl methacrylate, trimethylamonioethyl methacrylate), polyvinylacetates and mixtures thereof.

11. The dosage form according to claim 10, wherein the coating comprises at least one plastifier.

12. The dosage form according to claim 1, wherein the active principle is chosen from analgesics and particularly non opiate, low opiate analgesics, mixed opioids, morphinics or spasmodics, particularly hydrocodone, hydromorphone, morphine, oxycodone, oxymorphone, tramadol and derivatives thereof.

13. The dosage form according to claim 1, wherein the microgranules or the microtablets are conditioned in capsule form.

14. The dosage form according to claim 1, wherein the microgranules or the microtablets are conditioned in multiparticulate tablet form.

15. The dosage form according to claim 1, wherein the microgranules or the microtablets are conditioned in single dose packaging.