# US 8,465,769 B2 · Pharmaceutical composition with controlled active ingredient release for active ingredients with good solubility in water > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 8,465,769 B2 - Document ID: US8465769B2 - Status: Granted - Kind: B2 - Application number: 11/695,848 - Filed: 2007-04-03 - Published: 2008-02-21 - Granted: 2013-06-18 - Earliest claimed: 2006-08-18 - Assignees: Evonik Roehm GmbH - Applicants: Hans-Ulrich Petereit; Hema Ravishankar; Shradda Bodinge - Inventors: Hans-Ulrich Petereit; Hema Ravishankar; Shradda Bodinge - Web page: https://patentgrep.com/patent/US8465769B2 ## CPC - A61K 9/5078: {with drug-free core} - A61K 9/5026: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates} - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) ## Abstract A pharmaceutical preparation comprising: a) a core with an active ingredient and with an organic acid and/or the salt of an organic acid; and b) a coating which envelops the core and which comprises a polymer content of (meth)acrylate copolymers which have not more than 15% by weight of cationic or anionic groups, and which comprises at least 60% by weight of a (meth)acrylate copolymer which is composed of free-radically polymerized units of 93 to 98% by weight C1- to C4-alkyl esters of acrylic or of methacrylic acid and 7 to 2% by weight (meth)acrylate monomers having a quaternary ammonium group in the alkyl radical, wherein the active ingredient has a solubility in water of at least 10 g/l at 20° C. and the coating comprises silicon dioxide particles having an average particle size in the range from 1 to 50 μm. ## Claims ### Claim 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 C1- to C4-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. ### Claim 2 (depends on 1) 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 C1- to C4-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. ### Claim 3 (depends on 1) 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 C1- to C4-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 C1- to C4-alkyl esters of (meth)acrylic acid and 0-5% by weight (meth)acrylic acid. ### Claim 4 (depends on 1) 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. ### Claim 5 (depends on 1) The preparation according to claim 1, wherein the core, coating, or both comprise(s) at least one pharmaceutically acceptable excipient. ### Claim 6 (depends on 1) 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. ### Claim 7 (depends on 1) The preparation according to claim 1, wherein the polymer content of the coating together with the proportion of contained SiO2 totals 10 to 100% by weight based on the coating. ### Claim 8 (depends on 1) 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. ### Claim 9 (depends on 1) The preparation according to claim 1, wherein the silicon dioxide particles comprise precipitated silicon dioxide. ### Claim 10 (depends on 1) 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. ### Claim 11 (depends on 1) A tablet comprising the preparation according to claim 1. ### Claim 12 (depends on 1) A gelatin capsule containing the preparation according to claim 1. ### Claim 13 (depends on 1) 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. ### Claim 14 (depends on 1) The preparation according to claim 1, which is enveloped by a (meth)acrylate copolymer which comprises 10-60% by weight methacrylic acid monomers. ### Claim 15 (depends on 1) 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. ### Claim 16 (depends on 1) A method for producing a pharmaceutical preparation according to claim 1 comprising: coating the core with said coating. ### Claim 17 (depends on 1) 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. ### Claim 18 (depends on 17) The method of claim 17, wherein said pharmaceutical preparation is administered orally. ### Claim 19 (depends on 1) 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. ### Claim 20 (depends on 19) The method of claim 19, wherein said pharmaceutical preparation is administered orally. ### Claim 21 (depends on 1) The preparation of claim 1, wherein said core comprises a nonpareil. ### Claim 22 (depends on 1) 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. ### Claim 23 (depends on 1) 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. ### Claim 24 (depends on 1) 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.