Anti-misuse solid oral pharmaceutical form provided with a specific modified release profile

• US 20110091537A1
• Filed: 10/15/2010
• Published: 04/21/2011
• Est. Priority Date: 10/16/2009
• Status: Abandoned Application

• Current Assignee: Flamel Ireland, Ltd.
• Original Assignee: Flamel Technologies SA (Avadel Pharmaceuticals Plc)
• Inventors: DAVIAUD-VENET, Anne-Sophie, Castan, Catherine
• Application Number:
  US12/905,387
• Publication Number:
  US 20110091537A1
• Time in Patent Office: Days
• US Class Current: 424/452
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• 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 9/4808 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 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/26 Psychostimulants, e.g. nicotine, cocaine

Abstract

The present invention relates to a solid oral pharmaceutical form, with modified release of at least one active ingredient, containing at least microparticles containing said active ingredient and at least one viscosifying agent in a form isolated from said microparticles of active ingredient, characterized in that said microparticles possess an average diameter ranging from 100 to 600 μm, and are formed by a core containing at least said active ingredient and coated with at least one coating layer,

• • said core being formed by a support particle covered by a layer comprising at least said active ingredient,
  • said coating layer being formed by a material composed of at least 25 to 70% by weight relative to the total weight of said coating, of at least one polymer A insoluble in water, 30 to 75% by weight relative to the total weight of said coating, of at least one polymer B insoluble in water below pH 5 and soluble in water above pH 7, and 0 to 25% by weight relative to the total weight of said coating, of at least one plasticizer,
  • said polymers A and B being in a polymer(s) B/polymer(s) A weight ratio comprised between 0.25 and 4, and
  • said coating layer representing at least 35% by weight, relative to the total weight of said microparticle.

Claims

1. Solid oral pharmaceutical form with modified release of at least one active ingredient, containing at least microparticles containing said active ingredient and at least one viscosifying agent in a form isolated from said microparticles of active ingredient, characterized in that said microparticles possess an average diameter ranging from 100 to 600 μ

m, and are formed by a core containing at least said active ingredient and coated with at least one coating layer,

said core being formed by a support particle covered by a layer comprising at least said active ingredient,

said coating layer being formed by a material composed of at least;

25 to 70% by weight relative to the total weight of said coating, of at least one polymer A which is insoluble in water,

30 to 75% by weight relative to the total weight of said coating, of at least one polymer B which is insoluble in water below pH 5 and soluble in water above pH 7, and

0 to 25% by weight relative to the total weight of said coating, of at least one plasticizer,

said polymers A and B being in a polymer(s) B/polymer(s) A weight ratio comprised between 0.25 and 4, and

said coating layer representing at least 35% by weight, relative to the total weight of said microparticle.

2. Solid form according to claim 1, in which said microparticles of active ingredient are resistant to crushing.

3. Solid form according to claim 1, in which the coating of said microparticles of active ingredient contains less than 30% by weight of talc, relative to the total weight of said coating, preferably less than 20% by weight, in particular less than 10% by weight, more particularly less than 5% by weight, and even totally free of talc.

4. Solid form according to claim 1, in which the coating of the microparticles is composed of a single layer formed by said material.

5. Solid form according to claim 1, in which the coating arranged on the surface of the microparticles is present at a coating level ranging from 35 to 60% by weight by weight relative to the total weight of said microparticle.

6. Solid form according to claim 1, in which the coating arranged on the surface of the microparticles is obtained by spraying in a fluidized bed, of a solution containing at least said polymers A and B on granules obtained by the application to the surface of a support particle of a layer comprising at least said active ingredient.

7. Solid form according to claim 1, in which the polymer A is chosen from ethylcellulose, cellulose acetate butyrate, cellulose acetate, ammonio (meth)acrylate copolymers, poly(meth)acrylic acid esters, and mixtures thereof.

8. Solid form according to claim 1, in which the coating of the microparticles contains 30 to 65% by weight of polymer(s) A relative to its total weight.

9. Solid form according to claim 1, in which the polymer B is chosen from the methacrylic acid and methyl methacrylate copolymer(s), the methacrylic acid and ethyl acrylate copolymer(s) and mixtures thereof.

10. Solid form according to claim 1, in which the coating of the microparticles contains 30 to 70% by weight of polymer(s) B relative to its total weight.

11. Solid form according to claim 1, in which the coating of the microparticles is formed by at least one mixture comprising, as polymer A, at least ethylcellulose or cellulose acetate butyrate or ammonio (meth)acrylate copolymer or a mixture thereof, with, as polymer B, at least one methacrylic acid and ethyl acrylate copolymer or a methacrylic acid and methyl methacrylate copolymer or a mixture thereof.

12. Solid form according to claim 1, in which the coating comprises the polymers A and B in a polymer(s) B/polymer(s) A weight ratio comprised between 0.3 and 4.

13. Solid form according to claim 1, in which said support particle possesses an average diameter less than or equal to 300 μ

m.

14. Solid form according to claim 1, in which said coated microparticles possess an average diameter ranging from 150 to 350 μ

m.

15. Solid form according to claim 1, in which the viscosifying agent is in the form of microparticles, distinct from the microparticles with modified-release of active ingredient.

16. Solid form according to claim 1, characterized in that the viscosifying agent is chosen from:

the polyacrylic acids, in particular the carbomers,

the polyalkylene glycols, for example the polyethylene glycols,

the polyalkylene oxides, for example the polyethylene oxides or polyoxyethylene,

the polyvinylpyrrolidones,

the gelatins,

the polysaccharides, preferably chosen from sodium alginate, the pectins, guar gum, the xanthans, carrageenans, gellans, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose and carboxymethylcellulose,

and mixtures thereof.

17. Solid form according to claim 1, in which the viscosifying agent is a polyoxyethylene, in particular possessing a high molecular weight, and more particularly having an average molecular weight ranging from 1 million g/mole to approximately 8 million g/mole.

18. Solid form according to claim 1, in which the active ingredient is chosen from the amphetamines, analgesics, anorexigens, antidepressants, antiepileptics, antiparkinsonians, anxiolytics, barbiturates, benzodiazepines, hypnotics, narcotics in particular the opioids, the neuroleptics, psychostimulants and psychotropics.

19. Solid form according to claim 1, characterized in that the active ingredient is a narcotic, more particularly chosen from oxycodone, oxymorphone, hydromorphone, hydrocodone, tramadol and their pharmaceutically acceptable salts.

20. Solid form according to claim 1, characterized in that it is presented in the form of a tablet or gelatin capsule.

21. Solid form according to claim 1, characterized in that it comprises at least one sequestering agent in the form of microparticles distinct from microparticles of active ingredient.

22. Solid form according to claim 21, in which the sequestering agent is chosen from:

sodium dodecyl sulphate or sodium docusate;

quaternary ammonium salts, in particular tetradecyl trimethyl ammonium bromide or benzethonium chloride;

strongly acid cation exchange resins when the active ingredient in solution is cationic, or strongly basic anion exchange resins when the active ingredient in solution is anionic, according to the polarity of the active ingredient, and mixtures thereof,

and in particular, when the active ingredient in solution is in cationic form, from;

strongly acid cation exchange resins, such as the sulfonated copolymers of styrene and divinylbenzene, and

weakly acid cation exchange resins, such as the cross-linked copolymers of methacrylic acid and divinylbenzene or their salts.