PH-dependent controlled release pharmaceutical opioid composition with resistance against the influence of ethanol

Patent metadata

Field	Value
Publication number	US-9700520-B2
Application number	US-67840610-A
Country	US
Kind code	B2
Filing date	Sep 25, 2007
Priority date	Sep 21, 2007
Publication date	Jul 11, 2017
Grant date	Jul 11, 2017

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.

First claim

The invention claimed is:

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 by at least 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 comprises 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, and
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:
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.

2. The controlled release pharmaceutical composition according to claim 1 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 or copolymer is a copolymer composed of free-radical polymerized units of more than 95 up to 100% by weight C 1 - to C 4 -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 anionic polymer is a (meth)acrylate copolymer composed of free-radical polymerized units of 25 to 95% by weight C 1 - to C 4 -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 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.

9. 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.

10. The controlled release pharmaceutical composition according to claim 1 equipped with a sub coat or a top coat, or both.

11. The controlled release pharmaceutical composition according to claim 1 present in the form of coated pellets or minitablets with an overall average diameter in the range of from 100 to 3000 μm.

12. The controlled release pharmaceutical composition according to claim 1 wherein the resulting coated pellets have an overall average diameter in the range of between 100 to 700 μm.

13. The controlled release pharmaceutical composition according to claim 1 wherein the resulting coated pellets or minitablets have an overall average diameter in the range of between 1400 to 3000 μm.

14. 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 .

15. 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 .

16. The controlled release pharmaceutical composition according to claim 1 , wherein the water insoluble essentially neutral vinyl polymer or copolymer is composed of 20 to 40% by weight of ethyl acrylate, 60 to 80% by weight of methyl methacrylate and 0 to less than 5% by weight of acrylic acid or methacrylic acid, and the anionic polymer or copolymer consists of 10 to 30% by weight methyl methacrylate, 50 to 70% by weight methyl acrylate and 5 to 15% by weight methacrylic acid.

Assignees

• Petereit Hans-Ulrich
• Ravishankar Hema
• Samel Ashwini
• Evonik Roehm Gmbh

Inventors

• Petereit Hans-Ulrich
• Ravishankar Hema
• Samel Ashwini

Classifications

• A61P25/04

  Centrally acting analgesics, e.g. opioids · CPC title

• A61K9/5078 Primary

  with drug-free core · CPC title

• A61K9/501

  Inorganic compounds · CPC title

• A61K9/5026

  obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates · CPC title