PH-DEPENDENT CONTROLLED RELEASE PHARMACEUTICAL COMPOSITION FOR NON-OPIOIDS WITH RESISTANCE AGAINST THE INFLUENCE OF ETHANOL

• US 20110229562A1
• Filed: 09/24/2008
• Published: 09/22/2011
• Est. Priority Date: 09/24/2008
• Status: Active Grant

• Current Assignee: Evonik Operations GmbH (Rag-Stiftung)
• Original Assignee: Evonik Rã¶Hm GmbH (Rag-Stiftung)
• Inventors: Renner, Gerhard, Fürst, Thomas, Bär, Hans, Gottschalk, Michael
• Granted Patent: US 10,933,024 B2
• Time in Patent Office: Days
• US Class Current: 424/452
• CPC Class Codes: A61K 9/5078 with drug-free core
• CPC Class Codes: A61P 9/06 Antiarrhythmics
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 Antihypertensives

Abstract

The invention relates to a pH-dependent controlled release pharmaceutical composition, comprising at least one pharmaceutical active ingredient, with the exception of opioids, 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, characterized in that the coating layer further comprises 110 to 250% by weight of a non-porous inert lubricant, 1 to 35% by weight of at least one neutral cellulosic compound and 1 to 25% by weight of at least one emulsifier, each calculated on dry weight of the polymer mixture.

Claims

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

a core comprising at least one pharmaceutical active ingredient, with the exception of opioids,

wherein the core is coated by at least one coating layer controlling the release of the pharmaceutical composition,

the at least one coating layer comprises

(A) 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,

(B) 110 to 250% by weight of a non-porous inert lubricant,

(C) 1 to 35% by weight of at least one neutral cellulosic compound and

(D) 1 to 25% by weight of at least one emulsifier, and

(B), (C), and (D) are each calculated on dry weight of the polymer mixture.

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 comprising at least one free-radical polymerized unit of

more than 95 up to 100% by weight of at least one C₁- to C₄-alkyl ester 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 polymer or copolymer.

7. The controlled release pharmaceutical composition according to claim 1, wherein the water soluble anionic polymer is a (meth)acrylate copolymer comprising free-radical polymerized units ofto 95% by weight of at least one C₁- to C₄-alkyl ester of acrylic or of methacrylic acid, and

5 to 75% by weight of at least one (meth)acrylate monomer having an anionic group.

8. The controlled release pharmaceutical composition according to claim 7, wherein the water soluble anionic polymer comprises at least one free-radical polymerized unit ofto 30% by weight methyl methacrylate,to 70% by weight methyl acrylate, and

5 to 15% by weight methacrylic acid.

9. The controlled release pharmaceutical composition according to claim 1, wherein the neutral cellulosic compound is hydroxypropylmethylcellulose.

10. The controlled release pharmaceutical composition according to claim 1, wherein the emulsifier is a nonionic emulsifier.

11. The controlled release pharmaceutical composition according to claim 10, wherein the emulsifier is polyoxyethylene derivative of a sorbitan ester.

12. The controlled release pharmaceutical composition according to claim 10, wherein the emulsifier is a polyethoxy sorbitan monooleate.

13. 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 an addition of 40% (v/v) ethanol, the controlled release pharmaceutical composition has:

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

14. The controlled release pharmaceutical composition according to claim 1, wherein the pharmaceutical active ingredient is metoprolol or a pharmaceutically acceptable salt of metoprolol.

15. The controlled release pharmaceutical composition according to claim 1, wherein the controlled release pharmaceutical composition is in a form of pellet comprised in a multiparticulate pharmaceutical form selected from the group consisting of a compressed tablet, a capsule, a sachet, an effervescent tablet, and a reconstitutable powder.

16. The controlled release pharmaceutical composition according to claim 1, comprising at least one of a sub coat and a top coat.

17. The controlled release pharmaceutical composition according to claim 1, wherein the controlled release pharmaceutical composition is present in a form of at least one coated pellet with an overall average diameter in the range of from 100 to 5000 μ

m.

18. The controlled release pharmaceutical composition according to claim 17, wherein the at least one coated pellet has an overall average diameter in the range between 100 to 700 μ

m.

19. The controlled release pharmaceutical composition according to claim 17, wherein the at least one coated pellet has an overall average diameter in the range between 1400 to 5000 μ

m.

20. The controlled release pharmaceutical composition according to claim 19, wherein the coating layer is present in an amount of at least 30% by weight relative to a weight of core.

21. The controlled release pharmaceutical composition according to claim 1, wherein the active ingredient is released to a degree of 10% or less in simulated gastric fluid pH 1.2 with or without an addition of 40% ethanol (v/v) within 2 hours.

22. A process for preparing a controlled release pharmaceutical composition according to claim 1, comprising:

direct compressing the controlled release pharmaceutical composition,

compressing at least one dry, wet or sintered granule of the controlled release pharmaceutical composition, and subsequent rounding off,

wet or dry granulating or direct pelleting the controlled release pharmaceutical composition, or

binding at least one powder (powder layering) onto at least one active ingredient-free bead or neutral core (nonpareilles) or at least one active ingredient-containing particle and by applying the polymer coating in a spray process or by fluidized bed granulation.

23. A method for reducing a risk of enhanced or reduced release of the included pharmaceutical active ingredient after oral ingestion by simultaneous or subsequent consumption of ethanol containing drinks, comprising:

administering the controlled release pharmaceutical composition of claim 1 to a subject in need thereof.