Pharmaceutical composition with controlled active ingredient release for active ingredients with good solubility in water

1. A pharmaceutical preparation comprising a core that is enveloped by a coating;

wherein said core comprises an active ingredient, which has a solubility in water of at least 10 g/l at 20° C., and an organic acid, a salt of an organic acid, or both; and

wherein said coating comprises silicon dioxide particles having an average particle size ranging from 1 to 50 μm, and one or more (meth)acrylate copolymer(s), where at least 60% by weight of said copolymer(s) are free-radically copolymerized units containing 93 to 98% by weight C 1 - to C 4 -alkyl esters of acrylic or of methacrylic acid monomers and 2% to 7% by weight (meth)acrylate monomers having a quaternary ammonium group in the alkyl radical;

wherein said preparation contains said coating in an amount ranging from 10 to 200 wt. % based on the weight of the core; and

wherein said pharmaceutical preparation exhibits sigmoidal active ingredient release characteristics with a lag phase, a pulse phase and a run-out phase, characterized by an active ingredient release in the paddle apparatus at 100 rpm in buffer of pH 6.8 according to the European pharmacopoeia of approximately 10% during the lag phase and a subsequent active ingredient release of approximately a further 80% within less than 4 hours in the pulse phase.

2. The preparation according to claim 1 , wherein said one or more (meth)acrylate copolymers in the coating further comprise:

1-40% by weight of a (meth)acrylate copolymer which is composed of 85 to less than 93% by weight C 1 - to C 4 -alkyl esters of acrylic or of methacrylic acid and more than 7 to 15% by weight (meth)acrylate monomers having a quaternary ammonium group in the alkyl radical.

3. The preparation according to claim 1 , wherein the polymer content of the coating consists of a mixture of:

60 to 99% by weight of a (meth)acrylate copolymer which is composed of 93 to 98% by weight C 1 - to C 4 -alkyl esters of acrylic or of methacrylic acid and 2% to 7% by weight (meth)acrylate monomers having a quaternary ammonium group in the alkyl radical, and

1-40% by weight of a (meth)acrylate copolymer which is composed of 95 to 100% by weight C 1 - to C 4 -alkyl esters of (meth)acrylic acid and 0-5% by weight (meth)acrylic acid.

4. The preparation according to claim 1 , wherein trimethylammoniumethyl methacrylate chloride is present as (meth)acrylate monomer having a quaternary ammonium group in the alkyl radical in the (meth)acrylate copolymer.

5. The preparation according to claim 1 , wherein the core, coating, or both comprise(s) at least one pharmaceutically acceptable excipient.

6. The preparation according to claim 1 , wherein the lag phase ranges from 3.5 to 4.0 hours and the pulse phase ranges from 2.5 to 4.0 hours.

7. The preparation according to claim 1 , wherein the polymer content of the coating together with the proportion of contained SiO 2 totals 10 to 100% by weight based on the coating.

8. The preparation according to claim 1 , wherein said organic acid is selected from the group consisting of citric acid, fumaric acid, formic acid, acetic acid, maleic acid, succinic acid, tartaric acid, glutaric acid and lactic acid; or their ammonium, lithium, sodium or potassium salts; or mixtures thereof.

9. The preparation according to claim 1 , wherein the silicon dioxide particles comprise precipitated silicon dioxide.

10. The preparation according to claim 1 , comprising 5 to 50% by weight silicon dioxide particles based on the (meth)acrylate copolymer(s) present in the coating.

11. A tablet comprising the preparation according to claim 1 .

12. A gelatin capsule containing the preparation according to claim 1 .

13. The preparation according to claim 1 , wherein the organic acid and/or the salt of the organic acid forms an outer layer of the core.

14. The preparation according to claim 1 , which is enveloped by a (meth)acrylate copolymer which comprises 10-60% by weight methacrylic acid monomers.

15. The preparation according to claim 1 , comprising at least one of the following active ingredients or their water-soluble, pharmaceutically acceptable salts: acebutolol, amitryptyline, aripiprazole, atenolol, atropine, betaxolol, bisoprolol, bupavacaine, buproprion, butabarbital, carteolol, carvedilol, cefazoline, cefotaxime, chlorphenaramine, chlorpromazine, clindamycin, codeine, diltiazem, dimercaprol, diphenhydarmine, dopamine, doxylamine, duloxetine, flexainide, fluoxetine, fluphenazine, flurazepam, gentamycin, hydralazine, hydrocortisone, hydroquinone, hyoscyamine, isoniazid, isoproterenol, kanamycin, labetolol, lisinopril, metipranolol, mexiletine, morphine, nadolol, neomycin, norepinephrine, nortryptyline, ondansetron, oxprenolol, oxymetazoline, oxymorphone, paroxetine, penbutolol, phenylephrine, pindolol, prednisolone, primaquine, propranolol, pyrrocaine, sotalol, sulphadiazine, tamoxifen, terbutaline, timolol, tramadol, trazodone, triflupromazine, tetracycline, tubocurarine, venlafaxine, and verapamil.

16. A method for producing a pharmaceutical preparation according to claim 1 comprising:

coating the core with said coating.

17. A method for providing sigmoidal release of at least one active ingredient comprising:

administering the pharmaceutical preparation of claim 1 to a subject in need thereof;

wherein the sigmoidal release constitutes an initial lag phase wherein less than 10% of said active ingredient is released, and a subsequent pulse phase where an additional 80% of said active ingredient is released; and

wherein the pulse phase occurs in less than 4 hours.

18. The method of claim 17 , wherein said pharmaceutical preparation is administered orally.

19. A method for treating a disease or disorder comprising administering to a subject in need thereof an effective amount of the pharmaceutical preparation of claim 1 .

20. The method of claim 19 , wherein said pharmaceutical preparation is administered orally.

21. The preparation of claim 1 , wherein said core comprises a nonpareil.

22. The preparation of claim 1 , wherein the core further comprises polyvinylpyrrolidone in an amount ranging from 10% to 50% based on the weight of the core.

23. The preparation of claim 1 , wherein the core further comprises colloidal silica in an amount ranging from 10% to 50% based on the weight of the core.

24. The preparation of claim 1 , wherein the core further comprises polyvinylpyrrolidone and colloidal silica in an amount ranging from 10% to 50% based on the weight of the core and the coating comprises:

Copolymer 1: 65% by weight methyl methacrylate, 30% by weight ethyl acrylate and 5% by weight 2-trimethylammoniumethyl methacrylate chloride; and

Copolymer 2: 60% by weight methyl methacrylate, 30% by weight ethyl acrylate and 10% by weight 2-trimethylammoniumethyl methacrylate chloride.