PH-DEPENDENT CONTROLLED RELEASE PHARMACEUTICAL OPIOID COMPOSITION WITH RESISTANCE AGAINST THE INFLUENCE OF ETHANOL

• US 20100226978A1
• Filed: 09/25/2007
• Published: 09/09/2010
• Est. Priority Date: 09/21/2007
• Status: Active Grant

• Current Assignee: Evonik Operations GmbH (Rag-Stiftung)
• Original Assignee: Evonik Rã¶Hm GmbH (Rag-Stiftung)
• Inventors: Petereit, Hans-Ulrich, Samel, Ashwini, Ravishankar, Hema
• Granted Patent: US 9,700,520 B2
• Time in Patent Office: Days
• US Class Current: 424/459
• 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 9/5078 with drug-free core
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids

Abstract

The invention relates to a pH-dependent controlled release pharmaceutical composition, comprising a core, comprising at least one pharmaceutical active ingredient, which is an opioid, wherein the core is coated at least by one coating layer, controlling the release of the pharmaceutical composition, wherein the coating layer comprises a polymer mixture of i) 40-95% by weight, based on dry weight of the polymer mixture, of at least one water insoluble essentially neutral vinyl polymer, and ii) 5-60% by weight, based on dry weight of the polymer mixture, of at least one anionic polymer or copolymer, which is insoluble in a buffered medium below pH 4.0 and soluble at least in the range from pH 7.0 to pH 8.0, characterized in that the coating layer further contains 110 to 250% by weight, calculated on dry weight of the polymer mixture, of a non-porous inert lubricant and the coating layer is present in an amount of at least 60% by weight calculated on the weight of core.

Claims

1. A pH-dependent controlled release pharmaceutical composition, comprising

a core, comprising at least one pharmaceutical active ingredient, which is an opioid, wherein the core is coated at least by one coating layer, controlling the release of the pharmaceutical composition,

wherein the coating layer comprises a polymer mixture of

i) 40-95% by weight, based on dry weight of the polymer mixture, of at least one water insoluble essentially neutral vinyl polymer or copolymer, and

ii) 5-60% by weight, based on dry weight of the polymer mixture, of at least one anionic polymer or copolymer, which is insoluble in a buffered medium below pH 4.0 and soluble at least in the range from pH 7.0 to pH 8.0,

wherein

the coating layer further contains 110 to 250% by weight, calculated on dry weight of the polymer mixture, of a non-porous inert lubricant and the coating layer is present in an amount of at least 60% by weight calculated on the weight of core.

2. The controlled release pharmaceutical composition according to claim 1 characterized in that wherein the non-porous inert lubricant is a layered silica component, a pigment or a stearate compound.

3. The controlled release pharmaceutical composition according to claim 2 wherein the inert lubricant is talc.

4. The controlled release pharmaceutical composition according to claim 2 wherein the inert lubricant is Ca- or Mg-stearate.

5. The controlled release pharmaceutical composition according to claim 1, wherein the water insoluble essentially neutral vinyl polymer is a copolymer composed of free-radical polymerized units of more than 95 up to 100% by weight C₁- to C₄-alkyl esters of acrylic or of methacrylic acid and less than 5% by weight of acrylic or methacrylic acid.

6. The controlled release pharmaceutical composition according to claim 1, wherein the water insoluble essentially neutral polymer is a polyvinyl acetate type polymer or copolymer.

7. The controlled release pharmaceutical composition according to claim 1, wherein the water soluble anionic polymer is a (meth)acrylate copolymer composed of free-radical polymerized units of 25 to 95% by weight C₁- to C₄-alkyl esters of acrylic or of methacrylic acid and 5 to 75% by weight (meth)acrylate monomers having an anionic group.

8. The controlled release pharmaceutical composition according to claim 1, wherein under in-vitro conditions according to USP paddle, 100 rpm, buffered at pH 6.8 in a medium with and without the addition of 40% (v/v) ethanol, it has the following properties:

when the pharmaceutical active ingredient is released to a degree of less than 20% without the addition of 40% (v/v) ethanol, the difference in the release rate with the addition of 40% (v/v) ethanol is not more than plus or minus 15% of the corresponding release value without 40% (v/v) ethanol, and

when the pharmaceutical active ingredient is released to a degree of 20-80% without the addition of 40% (v/v) ethanol, the difference in the release rate with the addition of 40% (v/v) ethanol is not more than plus or minus 30% of the corresponding release value without 40% (v/v) ethanol.

9. The controlled release pharmaceutical composition according to claim 1, wherein the opioid comprises a member selected from the group consisting of morphine, codeine and thebaine, diamorphine (heroin), oxycodone, hydrocodone, dihydrocodeine, hydromorphone, oxymorphone, nicomorphine, methadone, levomethadyl acetate hydrochloride (LAAM), pethidine (meperidine), ketobemidone, propoxyphene, dextropropoxyphene, dextromoramide, bezitramide, piritramide, pentazocine or phenazocine, hydromorphine, hydrocodone, oxymorphone, oxycodone, buprenorphine, hydromorphone, levorphanol, tramadol, tilidine, sufentanil, pentozocine, nalbuphine, meptazinol, meperidine and fentanyl including pharmaceutically acceptable salts, free base or free acid forms or mixtures of said substances.

10. The controlled release pharmaceutical composition according to claim 1 wherein it is in the form of pellets contained in a multiparticulate pharmaceutical form of compressed tablets, capsules, sachets, effervescent tablets or reconstitutable powders.

11. The controlled release pharmaceutical composition according to claim 1 wherein it is equipped with a sub coat and/or a top coat.

12. The controlled release pharmaceutical composition according to claim 10 wherein it is present in the form of coated pellets with an overall average diameter in the range of from 100 to 3000 μ

m.

13. The controlled release pharmaceutical composition according to claim 10 wherein the coated pellets have with an overall average diameter in the range between 100 to 700 μ

m.

14. The controlled release pharmaceutical composition according to claim 10 wherein the coated pellets have with an overall average diameter in the range between 1400 to 3000 μ

m.

15. A process for preparing a controlled release pharmaceutical composition according to claim 1 in a manner known by direct compression, compression of dry, wet or sintered granules and subsequent rounding off, wet or dry granulation or direct pelleting or by binding powders (powder layering) onto active ingredient-free beads or neutral cores (nonpareilles) or active ingredient-containing particles and by applying the polymer mixture coating in a spray process or by fluidized bed granulation.

16-17. -17. (canceled)

18. A method of reducing the risk of enhanced or reduced release of an included pharmaceutical active ingredient after oral ingestion by simultaneous or subsequent consumption of ethanol containing drinks comprising employing a pH-dependent controlled release pharmaceutical composition according to claim 1.

19. A method of reducing the risk of abuse of an included pharmaceutical active ingredient by in-vitro extraction using ethanol containing media before oral ingestion comprising employing a pH-dependent controlled release pharmaceutical composition according to claim 1.