Protective coatings for acidic active ingredients

Abstract

Dosage forms provided with protective coatings in which a core comprising at least one acidic active ingredient is provided with at least one inner and one outer coating layer, where the outer layer comprises, as component A, a cationic polymer which is an emulsion polymer of N,N-diethylaminoethyl methacrylate and further monomers.

Claims

1. A dosage form provided with protective coatings, in which a core comprising at least one acidic active ingredient is provided with at least one inner and one outer coating layer, where the outer layer comprises, as component A, a cationic polymer which is an emulsion polymer of N,N-diethylaminoethyl methacrylate and further monomers, wherein the inner coating layer comprises a neutral water-soluble polymer comprising polyvinyl alcohols, polyalkylene glycol—polyvinyl alcohol graft copolymers, polyvinylpyrrolidones, vinylpyrrolidone—vinyl acetate copolymers, alkylated and hydroxyalkylated celluloses or starches or mixtures of such polymers, and wherein component A of the outer coating layer comprises a polymer obtained by free-radical polymerization of: a) N,N-diethylaminoethyl methacrylate, and b) at least one free-radically polymerizable compound selected from esters of α,β-ethylenically unsaturated mono- and dicarboxylic acids with C.sub.1-C.sub.8-alkanols; and wherein component A of the outer coating layer comprises a polymer of 43 to 47% by weight, based on the total weight of the monomers used for the polymerization, of N,N-diethylaminoethyl methacrylate a), and 53 to 57% by weight, based on the total weight of the monomers used for the polymerization, of at least one compound b).

2. The dosage form according to claim 1, wherein the at least one acidic active ingredient comprises an active ingredient with free carboxyl, sulfonic acid or phosphonic acid groups, acidic hydroxyl groups, acidic N—H groups or acidic C—H groups or mixtures of these active ingredients.

3. The dosage form according to claim 1, comprising acidic active ingredients with a pKa value between 6.5 and 0.5.

4. The dosage form according to claim 1, comprising acidic active ingredients with a pKa value between 5.0 and 1.0.

5. The dosage form according to claim 1, wherein the neutral polymer of the inner coating layer comprises polyvinyl alcohols, polyalkylene glycol—polyvinyl alcohol graft copolymers or mixtures thereof.

6. The dosage form according to claim 1, wherein component A comprises a polymer obtained with methyl methacrylate as monomer b).

7. The dosage form according to claim 1, wherein the outer coating layer further comprises, as component B, one or more antioxidants.

8. The dosage form according to claim 1, wherein the outer coating layer further comprises, as component B, one or more antioxidants selected from the group consisting of phenolic antioxidants, thiolic antioxidants, basic amino acids, alkali metal carbonates and alkali metal bicarbonates.

9. The dosage form according to claim 1, wherein the outer coating layer further comprises, as component C, one or more plasticizers.

10. The dosage form according to claim 1, wherein the outer coating layer further comprises, as component C, one or more plasticizers selected from the group consisting of tributyl citrate, acetyltributyl citrate, acetyltriethyl citrate, triacetin, triethyl citrate, diethyl sebacate and dibutyl sebacate.

11. The dosage form according to claim 1, wherein the outer coating layer further comprises, as component D, one or more pharmaceutical excipients selected from the group consisting of aroma substances, taste-improving substances, sweeteners, glidants, wetting agents, release agents, antiadhesives, stabilizers, pore formers, neutralizing agents, polishes, dyes, pigments, disinfectants or preservatives, and thickeners.

12. The dosage form according to claim 1, wherein the inner coating layer has a layer thickness of from 1 to 50 μm.

13. The dosage form according to claim 1, wherein the inner coating layer has a layer thickness of from 2 to 25 μm.

14. The dosage form according to claim 1, wherein the inner coating layer has a layer thickness of from 5 to 15 μm.

15. The dosage form according to claim 1, wherein the outer coating layer has a layer thickness of from 5 to 200 μm.

16. The dosage form according to claim 1, wherein the outer coating layer has a layer thickness of from 10 to 150 μm.

17. The dosage form according to claim 1, wherein the outer coating layer has a layer thickness of from 20 to 100 μm.

Description

DETAILED DESCRIPTION

(1) According to one or more embodiments of the present invention, provided are improved film coatings for pharmaceutical administration forms comprising acidic active ingredients which, even upon prolonged or thermally stressful storage, do not have any change in taste masking, protection against moisture and in the release behavior, and which do not have the disadvantages of the prior art.

(2) Accordingly, protective coatings and administration forms provided with such coatings have been found in which a core comprising at least one acidic active ingredient is provided with at least one inner and one outer coating layer, where the outer layer comprises a cationic polymer which is an emulsion polymer of N,N-diethylaminoethylmethacrylate and further monomers.

(3) Within the context of one or more embodiments of the invention, acidic active ingredients are understood as meaning active ingredients with free carboxyl, sulfonic acid or phosphonic acid groups, acidic hydroxyl groups, acidic N—H groups or acidic C—H groups. The pKa value of these active ingredients is between 6.5 and 0.5, preferably between 5.0 and 1.0. The pKa value refers the negative log.sub.10 log of the acid constant. The acid constant is usually ascertained by titration with hydroxide solution.

(4) The coating according to certain embodiments of the invention has an at least two-layer structure, with an inner layer consisting of a neutral water-soluble polymer and optionally pigments and further pharmaceutically customary excipients. A neutral water-soluble polymer is to be understood as meaning a polymer without acidic or basic group. Water-soluble means that at 25° C. at least 50 g are soluble in 1 L of water.

(5) In one or more embodiments, the outer layer comprises: i) as component A, a polymer obtained by free-radical polymerization, of a) N,N-diethylaminoethylmethacrylate, and b) at least one free-radically polymerizable compound selected from esters of α,β-ethylenically unsaturated mono- and dicarboxylic acids with C.sub.1-C.sub.8-alkanols, ii) optionally as component B, one or more antioxidants, iii) optionally as component C, one or more plasticizers, iv) optionally as component D, further pharmaceutical excipients.

(6) Water-soluble polymers of the inner layer which can be used are:

(7) polyvinyl alcohols, polyalkylene glycol—polyvinylalcohol graft copolymers, polyvinylpyrrolidones, vinylpyrrolidone—vinylacetate copolymers, alkylated and hydroxyalkylated celluloses or starches, such as e.g. hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose, hydroxyethylstarch.

(8) The layer thickness of the inner layer can be 1 to 50 μm, preferably 2 to 25 μm and particularly preferably 5 to 15 μm.

(9) The layer thickness of the outer layer can be 5 to 200 μm, preferably 10 to 150 μm and particularly preferably 20 to 100 μm.

(10) In certain embodiments, the coating compositions used for the outer layer are based on aqueous polymer dispersions which are obtained by free-radical emulsion polymerization of a monomer mixture M) comprising a) N,N-diethylaminoethylmethacrylate, and b) at least one free-radically polymerizable compound selected from esters of α,β-ethylenically unsaturated mono- and dicarboxylic acids with C.sub.1-C.sub.8-alkanols, in an aqueous medium at a pH of at least 8.

(11) The coating compositions in the form of aqueous polymer dispersions preferably comprise no additional organic solvents.

(12) According to particular embodiments of the invention, the coating compositions serve for producing pharmaceutical dosage forms which should be rapid-releasing in the acidic environment of the stomach. I.e. the coatings are soluble in gastric juice. In this connection, rapidly-releasing means that after 60 min at least 80% of the active ingredient has been released. Coatings obtained according to embodiments of the invention should not dissolve in the oral cavity and throat in the neutral or virtually neutral environment of the saliva.

(13) The coating compositions invention can be used for masking taste or for protecting against moisture. The water vapor permeability of the coatings is very low, as a result of which moisture-sensitive active ingredients are protected.

(14) Component A

(15) Monomer a)

(16) According to certain embodiments of the invention, N,N-diethylaminoethylmethacrylate is used as monomer a).

(17) To produce the aqueous polymer dispersions Pd) according to the invention, the component a) is used preferably in an amount of from 25 to 65% by weight, particularly preferably 30 to 60% by weight, in particular 38 to 48% by weight, specifically 43 to 47% by weight, based on the total weight of the monomers used for the polymerization.

(18) Monomer b)

(19) In one or more embodiments, the component b) is selected from esters of alpha, beta-ethylenically unsaturated mono- and dicarboxylicacids with C.sub.1-C.sub.8-alkanols.

(20) Suitable compounds b) are methyl(meth)acrylate, methylethacrylate, ethyl(meth)acrylate, ethylethacrylate, n-propyl(meth)acrylate, isopropyl(meth)acrylate, n-butyl(meth)acrylate, sec-butyl(meth)acrylate, tert-butyl(meth)acrylate, tertbutylethacrylate, n-hexyl(meth)acrylate, n-heptyl(meth)acrylate, n-octyl(meth)acrylate, 1,1,3,3-tetramethylbutyl(meth)acrylate and ethylhexyl(meth)acrylate.

(21) As component b), particular preference is given to using methylmethacrylate or a monomer mixture comprising methylmethacrylate.

(22) To produce the aqueous polymer dispersions, the component b) is used preferably in an amount of from 35 to 75% by weight, particularly preferably 40 to 70% by weight, in particular 52 to 62% by weight, specifically 53 to 57% by weight, based on the total weight of the monomers used for the polymerization.

(23) Monomer c)

(24) The monomer mixtures M) used for producing the polymer dispersions can additionally comprise at least one further monomer c). The additional monomers c) are preferably selected from esters of alpha, beta-ethylenically unsaturated mono- and dicarboxylicacids with C.sub.9-C.sub.30-alkanols and C.sub.2-C.sub.30-alkanediols, amides of alpha, beta-ethylenically unsaturated mono- and dicarboxylic acids with C.sub.2-C.sub.30-amino alcohols which have a primary or secondary amino group, primary amides of alpha, beta-ethylenically unsaturated monocarboxylic acids and N-alkyl and N,N-dialkyl derivatives thereof, N-vinyllactams, open-chain N-vinyl amide compounds, esters of vinyl alcohol and allylalcohol with C.sub.1-C.sub.30-monocarboxylic acids, vinyl ethers, vinyl aromatics, vinyl halides, vinylidene halides, C.sub.2-C.sub.8-mono olefins, unsaturated nitriles, non-aromatic hydrocarbons with at least two conjugated double bonds and mixtures thereof.

(25) Suitable additional monomers c) are esters of alpha, beta-ethylenically unsaturated mono- and dicarboxylic acids with C.sub.9-C.sub.30-alkanols, such as n-nonyl(meth)acrylate, n-decyl(meth)acrylate, n-undecyl(meth)acrylate, tridecyl(meth)acrylate, myristyl(meth)acrylate, pentadecyl(meth)acrylate, palmityl(meth)acrylate, heptadecyl(meth)acrylate, nonadecyl(meth)acrylate, arachinyl(meth)acrylate, behenyl(meth)acrylate, lignoceryl(meth)acrylate, cerotinyl(meth)acrylate, melissinyl(meth)acrylate, palmitoleinyl(meth)acrylate, oleyl(meth)acrylate, linolyl(meth)acrylate, linolenyl(meth)acrylate, stearyl(meth)acrylate, lauryl(meth)acrylate and mixtures thereof.

(26) Suitable additional monomers c) are also esters of alpha, beta-ethylenically unsaturatedmono- and dicarboxylic acids with C.sub.2-C.sub.30-alkanediols, such as 2-hydroxyethylacrylate, 2-hydroxyethylmethacrylate, 2-hydroxyethylethacrylate, 2-hydroxypropylacrylate, 2-hydroxypropylmethacrylate, 3-hydroxypropylacrylate, 3-hydroxypropylmethacrylate, 3-hydroxybutylacrylate, 3-hydroxybutylmethacrylate, 4-hydroxybutylacrylate, 4-hydroxybutylmethacrylate, 6-hydroxyhexylacrylate, 6-hydroxyhexylmethacrylate, 3-hydroxy-2-ethylhexylacrylate, 3-hydroxy-2-ethylhexylmethacrylate etc.

(27) Suitable additional monomers c) are also primary amides of alpha, beta-ethylenically unsaturated monocarboxylic acids and N-alkyl and N,N-dialkyl derivatives thereof, such as acrylamide, methacrylamide, N-methyl(meth)acrylamide, N-ethyl(meth)acrylamide, N-propyl(meth)acrylamide, N-(n-butyl)(meth)acrylamide, N-(tert-butyl)(meth)acrylamide, N-(n-octyl)(meth)acrylamide, N-(1,1,3,3-tetramethylbutyl)(meth)acrylamide, N-ethylhexyl(meth)acrylamide, N-(n-nonyl)(meth)acrylamide, N-(n-decyl)(meth)acrylamide, N-(n-undecyl)(meth)acrylamide, N-tridecyl(meth)acrylamide, N-myristyl(meth)acrylamide, N-pentadecyl(meth)acrylamide, N-palmityl(meth)acrylamide, N-heptadecyl(meth)acrylamide, N-nonadecyl(meth)acrylamide, N-arachinyl(meth)acrylamide, N-behenyl(meth)acrylamide, N-lignoceryl(meth)acrylamide, N-cerotinyl(meth)acrylamide, N-melissinyl(meth)acrylamide, N-palmitoleinyl(meth)acrylamide, N-oleyl(meth)acrylamide, N-linolyl(meth)acrylamide, N-linolenyl(meth)acrylamide, N-stearyl(meth)acrylamide, N-lauryl(meth)acrylamide, N,N-dimethyl(meth)acrylamide, N,N-diethyl(meth)acrylamide, morpholinyl(meth)acrylamide.

(28) Suitable additional monomers c) are also N-vinyllactams and derivatives thereof, which can have e.g. one or more C.sub.1-C.sub.6-alkylsubstituents, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl etc. These include e.g. N-vinyl pyrrolidone, N-vinyl piperidone, N-vinyl caprolactam, N-vinyl-5-methyl-2-pyrrolidone, N-vinyl-5-ethyl-2-pyrrolidone, N-vinyl-6-methyl-2-piperidone, N-vinyl-6-ethyl-2-piperidone, N-vinyl-7-methyl-2-caprolactam, N-vinyl-7-ethyl-2-caprolactam etc. Preference is given to using N-vinyl pyrrolidone and N-vinyl caprolactam.

(29) Open-chain N-vinyl amide compounds suitable as monomers c) are, for example, N-vinyl formamide, N-vinyl-N-methylformamide, N-vinylacetamide, N-vinyl-N-methylacetamide, N-vinyl-N-ethylacetamide, N-vinyl propionamide, N-vinyl-N-methylpropionamide and N-vinyl butyramide.

(30) Suitable additional monomers c) are also vinylacetate, vinyl propionate, vinyl butyrate and mixtures thereof.

(31) Suitable additional monomers c) are also ethylene, propylene, isobutylene, butadiene, styrene, alpha-methylstyrene, acrylonitrile, methacrylonitrile, vinylchloride, vinylidene chloride, vinylfluoride, vinylidene fluoride and mixtures thereof.

(32) The additional monomers c) specified above can be used individually or in the form of any desired mixtures.

(33) To produce the aqueous polymer dispersions, the component c) is used preferably in an amount of from 0 to 80% by weight, based on the total weight of the monomers used for the polymerization. A specific embodiment relates to polymer dispersions Pd) which comprise no additional monomer c) in copolymerized form. If present, the component c) is used preferably in an amount of from 0.1 to 70% by weight, particularly preferably 1 to 60% by weight, in particular 5 to 50% by weight, based on the total weight of the monomers used for the polymerization.

(34) Preferably, no monomer c) is used.

(35) Monomer d)

(36) The monomer mixtures M) used to produce the polymer dispersions can comprise, in copolymerized form, in addition to the compound a), at least one further compound d) different there from having a free-radically polymerizable alpha,beta-ethylenically unsaturated double bond and at least one cationogenic and/or cationic group per molecule.

(37) Preferably, the cationogenic or cationic groups of component d) are nitrogen-containing groups, such as primary, secondary and tertiary amino groups and quaternary ammonium groups. Preferably, the nitrogen-containing groups are tertiary amino groups or quaternary ammonium groups. Charged cationic groups can be produced from the amine nitrogens either by protonation, e.g. with monobasic or polybasic carboxylic acids, such as lactic acid or tartaric acid, or mineral acids, such as phosphoric acid, sulfuric acid and hydrochloric acid, or by quaternization, e.g. with alkylating agents, such as C.sub.1-C.sub.4-alkylhalides or sulfates. Examples of such alkylating agents are ethylchloride, ethylbromide, methylchloride, methylbromide, dimethylsulfate and diethylsulfate.

(38) Suitable compounds d) are e.g. the esters, different from DEAEMA, of alpha, beta-ethylenically unsaturated mono- and dicarboxylic acids with amino alcohols. Preferred amino alcohols are C.sub.2-C.sub.12-aminoalcohols which are C.sub.1-C.sub.8-mono- or dialkylated on the amine nitrogen. Suitable acid components of these esters are e.g. acrylic acid, methacrylic acid, fumaric acid, maleic acid, itaconic acid, crotonic acid, maleic anhydride, monobutylmaleate and mixtures thereof. Preference is given to using acrylic acid, methacrylic acid and mixtures thereof as acid component of these esters.

(39) Suitable additional compounds d) are N,N-dimethylaminomethyl(meth)acrylate, N,N-dimethylaminoethyl(meth)acrylate, N,N-diethylaminoethylacrylate, N,N-dimethylaminopropyl(meth)acrylate, N,N-diethylaminopropyl(meth)acrylate and N,N-dimethylaminocyclohexyl(meth)acrylate.

(40) Suitable monomers d) are also the amides of the aforementioned alpha, beta-ethylenically unsaturated mono- and dicarboxylic acids with diamines which have at least one primary or secondary amino group. Preference is given to diamines which have one tertiary and one primary or secondary amino group.

(41) These include N-[2-(dimethylamino)ethyl]acrylamide, N-[2-(dimethylamino)ethyl]methacrylamide, N-[3-(dimethylamino)propyl]acrylamide, N-[3-(dimethylamino)propyl]methacrylamide, N-[4-(dimethylamino)butyl]acrylamide, N-[4-(dimethylamino)butyl]methacrylamide, N-[2-(diethylamino)ethyl]acrylamide, N-[4-(dimethylamino)cyclohexyl]acrylamide, N-[4-(dimethylamino)cyclohexyl]methacrylamide etc.

(42) Suitable monomers d) are also N,N-diallylamines and N,N-diallyl-N-alkylamines and acid additions salts and quaternization products thereof. Alkyl here is preferably C.sub.1-C.sub.24-alkyl. Preference is given to N,N-diallyl-N-methylamine and N,N-diallyl-N,N-dimethylammonium compounds, such as e.g. the chlorides and bromides.

(43) Suitable monomers d) are also vinyl- and allyl-substituted nitrogen heterocycles, such as N-vinylimidazole, N-vinyl-2-methylimidazole, vinyl- and allyl-substituted heteroaromatic compounds, such as 2- and 4-vinylpyridine, 2- and 4-allylpyridine, and the salts thereof.

(44) To produce the aqueous polymer dispersions Pd), the monomer d), if present, is used preferably in an amount such that the sum of the amounts of the monomers a) and of the monomers d) is in a range from 25 to 65% by weight, particularly preferably 30 to 60% by weight, based on the total weight of the monomers used for the polymerization.

(45) To produce the aqueous polymer dispersions Pd), the component d) is used preferably in an amount of from 0 to 50% by weight, based on the total weight of the monomers used for the polymerization.

(46) As already explained, it has surprisingly been found that the polymer dispersions Pd) used according to certain embodiments of the invention, based on DEAEMA (component a)), have a particularly good profile of properties. This profile of properties can as a rule be achieved without using further monomers having cationogenic/cationic groups. One specific embodiment therefore relates to polymer dispersions Pd) that do not comprise an additional monomer d) in copolymerized form.

(47) If present, the component d) is used preferably in an amount of from 0.1 to 40% by weight, particularly preferably 1 to 30% by weight, in particular 2 to 25% by weight, based on the total weight of the monomers used for the polymerization.

(48) In one particularly preferred embodiment of the process according to the invention, a monomer mixture M) is used that consists of 43 to 47% by weight, based on the total weight of the monomers used for the polymerization, of N,N-diethylaminoethylmethacrylate a), and 53 to 57% by weight, based on the total weight of the monomers used for the polymerization, of at least one compound b), in particular methylmethacrylate.

(49) As regards the preparation of the polymers by free-radical emulsion polymerization, reference is made here expressly to the disclosure of WO 2009/016258, in which the preparation and preferred embodiments are described in detail.

(50) The polymers present in the dispersions preferably have an average molecular weight M.sub.w, determined by means of gel permeation chromatography, in the range from 30 000 to 500 000, particularly preferably 60 000 to 140 000, in particular 80 000 to 120 000 g/mol.

(51) The polymers present in the dispersions Pd) preferably have a K value (determined in accordance with Fikentscher on a 1% strength solution in N-methylpyrrolidone (NMP)) in the rangefrom 40 to 60.

(52) The glass transition temperature T.sub.G (determined by means of DSC) is preferably in a range from 40 to 70° C., particularly preferably 52 to 62° C.

(53) The polymers present in the dispersions are essentially random copolymers.

(54) The average particle diameter of the polymer particles present in the polymer dispersion (determined by means of analytical ultracentrifuge) is preferably in a range from 70 to 200 nm, particularly preferably from 80 to 150 nm, in particular from 90 to 120 nm. The particle size distribution is preferably essentially unimodal.

(55) The LT value of the dispersions, determined on a 0.01% strength dispersion in water (2.5 cm cuvette, white light) is preferably at least 70%, particularly preferably at least 80%. Determination of the light transmission is described e.g. in Dieter Distler, Wässrige Polymerdispersionen [Aqueous polymer dispersions], Wiley-VCH (1999), p. 40.

(56) The solids content of the dispersions is preferably 10 to 50% by weight, particularly preferably 20 to 40% by weight. In the case of a purification of the dispersion by means of ultrafiltration, the dispersions preferably have solids contents that are within these ranges before and after the ultrafiltration. It is of course likewise possible to subject a diluted polymer dispersion to a concentration by ultrafiltration.

(57) The dispersions used for taste masking have, e.g. even at a solids content of 30% by weight, extremely low viscosities of preferably less than 50 mPas, particularly preferably less than 25 mPas and in particular less than 10 mPas (values determined by means of Brookfield viscometer at 20° C. and 100 s.sup.−1). Such low viscosities are of particular importance for many applications.

(58) The charge of the polymers present in the dispersions according to the invention is dependent on the pH of the dispersion. The isoelectric point is preferably in a pH range from about 7.5 to 8.5. The finished dispersion preferably has a pH in the range from 8 to 10, particularly preferably from 8.5 to 9.5 (at a solids content of 30% by weight). It is advantageous for the pH of the finished dispersion to be selected higher (more alkaline) than its isoelectric point provided dissolution or swelling of the polymer particles present in the dispersion is not desired. The dispersions are therefore preferably basic dispersions.

(59) The polymer dispersions are notable for their pH-dependent solubility. The pH range in which the dispersion dissolves upon acidification can be adjusted e.g. by the copolymerized amount of N,N-diethylaminoethylmethacrylate (monomer a) and optionally the use of further monomers with cationogenic/cationic groups (monomer d). Preferably, the polymers present in the polymer dispersions Pd) dissolve at a pH of at most 6.8, particularly preferably at a pH of at most 6.0.

(60) According to one preferred embodiment, polymer dispersions are used which comprise a polymer which comprises, in copolymerized form, 43 to 47% by weight, based on the total weight of the monomers used for the polymerization, of N,N-diethylaminoethylmethacrylate a), and 53 to 57% by weight, based on the total weight of the monomers used for the polymerization, of at least one compound b) as the only monomers.
Component B

(61) The coating compositions of the outer layer comprise, in addition to the polymer, one or more antioxidants or a combination of antioxidants.

(62) Of suitability in principle for improving the release stability as antioxidants are primarily the following agents, listed combinations or further combinations:

(63) N-acetylcysteine, allantoin, arginine, arginine+butylhydroxytoluene, arginine+N-acetylcysteine, ascorbylpalmitate, aspartic acid, biotin, butylhydroxyanisole, butylhydroxytoluene, butylhydroxytoluene+calcium carbonate, butylhydroxytoluene+Na-EDTA, butylhydroxytoluene+N-acetylcysteine calcium-bis[monoethyl(3,5-di-tert-butyl-4-hydroxybenzyl)phosphonate], catechol, citric acid, cysteamine, ethylhexylthioglycolate, gallic acid, hypophosphorous acid, caffeic acid, potassium iodide, creatine, creatinine, copper(I)chloride, copper(II)chloride, lysine, MEHQ, methionine, Na-EDTA, sodium carbonate, sodium dihydrogenphosphate, disodium hydrogenphosphate, sodium propionate, nordihydroguaiaretic acid, orotic acid, penicillamine, phosphoric acid, propylgallate, resveratrol, riboflavin, spermidine, thioglycolic acid, tocopherol, tocopherolacetate, trometamol, tyrosine, tartaric acid.

(64) Of suitability in principle for improving the stability against yellowing are primarily the following agents, listed combinations or further combinations:

(65) oleic acid, simethicone, butylhydroxytoluene, sodiumhydrogensulfite, tocopherol, sodium dihydrogencitrate, sodium hypochlorite, sodium hypophosphite, disodium hydrogenphosphate, tocopherol, tocopherolacetate, arginine, butylhydroxytoluene+Na-EDTA, acetylcysteine (N-acetylcysteine), butylhydroxytoluene, allantoin, butylhydroxyanisole, sodium carbonate, cysteamine, N-acetylcysteine.

(66) Preferred antioxidants are compounds of the phenol type. Preferred phenolic compounds are, for example, butylhydroxytoluene or butylhydroxyanisole, as they completely prevent both delay in dissolution and yellowing. Further suitable products are: catechol, gallic acid or esters thereof, tocopherol, caffeic acid, hydroquinone monomethylether (MEHQ), nordihydroguaiaretic acid, resveratrol.

(67) Likewise preferred antioxidants are thiolic compounds, such as N-acetylcysteine, cysteamine, thioglycolic acid.

(68) Furthermore, preference is given to basic amino acids such as arginine and lysine.

(69) Preferred antioxidants are also alkali metal carbonates or alkali metal bicarbonates, in particular the sodium salts, preferably sodium carbonate.

(70) Preference is also given to combinations with EDTA, in particular Na-EDTA or with citric acid.

(71) Particular preference is given to N-acetylcysteine, arginine, lysine, butylhydroxytoluene, butylhydroxytoluene+Na EDTA, and also sodium carbonate or combinations thereof.

(72) All of the stated compounds or classes of compounds can also be used in combination.

(73) The antioxidants are used in amounts of from 0.1 to 30, preferably 0.3 to 20, particularly preferably 0.5 to 12% by weight, based on the total amount of the solid in the coating composition.

(74) Component C

(75) Furthermore, the coating compositions according to the invention comprise plasticizers, preferably lipophilic plasticizers, as component C. Particularly suitable plasticizers are tributylcitrate, acetyltributylcitrate, acetyltriethylcitrate, triacetin, triethylcitrate, diethylsebacate and dibutyl sebacate.

(76) Components D

(77) The coating compositions used according to the invention for pharmaceutical administration forms can comprise, as components D, additionally at least one further pharmaceutically acceptable excipient. Of pharmaceutical acceptability are the excipients known for use in the field of pharmacy, food technology and related fields, in particular those listed in the relevant pharmacopoeia (e.g. Ph. Eur., USP, JP), and other excipients whose properties do not prohibit a physiological application.

(78) Suitable excipients may be: aroma substances, taste-improving substances, sweetening agents (sugars, sugar alcohols, sweeteners such as e.g. aspartame, saccharine-Na, sodium cyclamate), glidants, wetting agents, release agents, anti-adhesives, stabilizers, pore formers, neutralizing agents, gloss agents, dyes, pigments, disinfectants or preservatives, thickeners, etc. Such substances are described e.g. in Fiedler, H. P. Lexikon der Hilfsstoffe fürPharmazie, Kosmetikund angrenzende Gebiete [Lexicon of excipients for pharmacy, cosmetics and related fields], 4th edition, Aulendorf: ECV-Editio-Cantor-Verlag, 1996.

(79) Customary amounts of the excipients are in a range of in each case from 0 to 70% by weight, preferably from 0 to 60% by weight, in particular 1 to 50% by weight, based on the total weight of the solid in the coating composition.

(80) The coating compositions which are used for producing the outer coating layer can comprise, based on the total weight of the aqueous dispersion, i) 1 to 45% by weight of component A, ii) 0.01 to 15% by weight of component B, iii) 0.1 to 15% by weight of component C, iv) 0 to 35% by weight of components D.

(81) Preferred coating compositions comprise i) 1.5 to 42.5% by weight of component A, ii) 0.02 to 10% by weight of component B, iii) 0.15 to 12.5% by weight of component C, iv) 0 to 30% by weight of components D.

(82) Particularly preferred coating compositions comprise, based on the total weight of the dispersion, i) 4 to 40% by weight of component A, ii) 0.05 to 6% by weight of component B, iii) 0.4 to 8% by weight of component C, iv) 0.1 to 20% by weight of components D.

(83) The coating compositions both for the inner and outer layer can be produced e.g. by intimate mixing of a polymer dispersion or polymer solution, or a polymer obtainable there from by a drying process.

(84) The coating compositions can be used e.g. in powder form, as melt or in aqueous emulsion by granulation, pouring, spreading or by means of spray application. Preference is given to application as polymer dispersion, specifically as primary dispersion. The coating compositions can additionally comprise at least one further polymer component. In this connection, it is possible to use mixtures of at least two dispersions, at least one dispersion and at least one solution, at least one dispersion and at least one powder, at least two powders, etc.

(85) The coating compositions according to the invention are suitable for dosage forms of in principle any desired pharmaceutical active ingredients with acidic groups, which can preferably be administered in isolated or protected form, such as antidepressants, beta receptor blockers, anti-diabetics, analgesics, antiphlogistics, antirheumatics, antihypotonics, antihypertonics, psychopharmaceuticals, tranquilizers, antiemetics, muscle relaxants, glucocorticoids, agents for treating Colitis ulcerosa or Crohn's disease, antiallergics, antibiotics, antiepileptics, anticoagulants, antimycotics, antitussives, arteriosclerosis drugs, diuretics, enzymes, enzyme inhibitors, gout remedies, hormones and inhibitors thereof, cardiac glycosides, immunotherapeutics and cytokines, laxatives, antilipemics, gastrointestinal therapeutics, migraine remedies, preparations of minerals, otologics, Parkinson's drugs, thyroid therapeutics, spasmolytics, platelet aggregation inhibitors, vitamins, cytostatics and metastasis inhibitors, phytopharmaceuticals, chemotherapy drugs, nutraceuticals, vitamins, carotenoids and amino acids.

(86) Examples of suitable acidic active ingredients are:

(87) aceclofenac, acediasulfone, acedoben, aceglutamide, acemetacin, acetoxyvalerenic acid, acetylcysteine, acetylleucine, acetylmethionine, acetylsalicylic acid, acexamic acid, acifluorfen, acipimox, acitazanolast, acitretin, aconiazide, acrivastine, actarit, adapalene, adipiodone, alacepril, alatrofloxacin, alclofenac, alitame, alitretinoin, alliin, alminoprofen, alprostadil, alvimopan, amfenac, amineptine, aminocaproic acid, aminohippuric acid, 5-aminolevulinic acid, aminomethylbenzoic acid, aminopyralid, aminosalicylic acid, amlexanox, amoxicillin, ampicillin, amphotericin B, argatroban, arsenamide, artesunate, aspartame, aspoxicillin, atorvastatin, aurintricarboxylic acid, aurothiomalic acid, aviglycine, aviptadil, azelaic acid, azidocillin, azlocillin, azoximer bromide, aztreonam, baclofen, balofloxacin, balsalazide, benazepril, benazolin, bendamustine, bendazac, bensuldazic acid, bensulfuron, bentazon, bentiacide, bentiromide, benzylpenicilline, phenoxymethylpenicilline, bepotastine, beraprost, betamipron, betanin, bexarotene, bezafibrate, bilanafos, biotin, bivalirudin, beta-boswellic acid, bromfenac, bucillamine, bumadizone, bumetanide, buthiopurine, butibufen, C12 peptide, calcitonin, canrenoic acid, capobenic acid, captopril, carbenicillin, carbenoxolone, carbidopa, carbocisteine, carboprost, carfecillin, carfentrazone, carglumic acid, carindacillin, carnosine, carprofen, carumonam, carzenide, cefacetrile, cefaclor, cefadroxil, cefalexin, cefaloglycin, cefaloridine, cefalotin, cefamandole, cefapirin, cefatrizine, cefazolin, cefbuperazone, cefdinir, cefepime, cefixime, cefinenoxime, cefinetazole, cefminox, cefodizime, cefonicid, cefoperazone, ceforanide, cefoselis, cefotaxime, cefotetan, cefotiam, cefovecin, cefoxazole, cefoxitin, cefozopran, cefpimizole, cefpiramide, cefprozil, cefradine, cefroxadine, cefsulodin, ceftazidime, ceftezole, ceftibuten, ceftiofur, ceftizoxime, ceftriaxone, cefuroxime, cefuzonam, ceruletide, cetirizine, cetraxate, chenodeoxycholic acid, chloramben, chlorambucil, chondroitin sulfate, chromocarb, ciclacilin, cicloxilic acid, cilastatin, cilazapril, cinametic acid, cinoxacin, ciprodex, ciprofibrate, ciprofloxacin, clanobutin, clavulanic acid, clidanac, clinofibrate, clofencet, clonixin, cloprop, clopyralid, clorazepate, cloxacillin, cloxyfonac, corticorelin, cromoglicic acid, cyclanilide, cyclobutyrol, cynarine, dalapon, daminozide, danofloxacin, daptomycin, deferasirox, dehydrocholic acid, delapril, dexibuprofen, dexketopropfen, dexlipotam, dextrothyroxine, diacerein, dibromotyrosine, dicamba, dichlorprop, dichlorprop-P, diclofenac, diclofop, dicloxacillin, difenoxin, difloxacin, diflufenzopyr, diflunisal, diiodotyrosine, dikegulac, dimecrotic acid, dinoprost, dinoprostone, divalproex, D-luciferin, doconexent, doripenem, D-penicillamine, droxidopa, ecabet, eflornithine, eltenac, eltrombopag, enalapril, enalaprilat, endothal, enfenamic acid, enfuvirtide, enkorten, enoxacin, enoxolone, enrofloxacin, epalrestat, epoetin alfa, epoprostenol, eprosartan, eptifibatide, erdosteine, ertapenem, erythrosine, escin, etacrynic acid, etodolac, exenatide, faropenem, febuxostat, felbinac, fenbufen, fenchlorazole, fencibutirol, fendizoic acid, fenofibric acid, fenoprofen, fenoxaprop, fenoxaprop-P, fentiazac, fexofenadine, flavodic acid, fleroxacin, flomoxef, fluazifop, fluazifop-P, flucloxacillin, flufenamic acid, flumequine, flumiclorac, flunixin, flunoxaprofen, fluorodopa F18, flupropanate, fluprostenol, flupyrsulfuron, flurbiprofen, folic acid, folinic acid, fostosal, fosinopril, fudosteine, fumagillin, furosemide, fusidic acid, gabapentin, gadobenic acid, gadobutrol, gadodiamide, gadofosveset, gadopentetic acid, gadoteric acid, gadoxetic acid, gamma-aminobutyric acid, gamolenic acid, garenoxacin, gatifloxacin, gemfibrozil, gemifloxacin, gentisic acid, gibberrellic acid, gibberellin A4, gibberellin A7, glucagon, glufosinate, glycopine, glycyrrhizin, glyphosate, halazone, hetacillin, hyaluronic acid, ibafloxacin, ibuprofen, icatibant, icosapent, iloprost, imazamox, imazapic, imazapyr, imazaquin, imazethapyr, imidapril, imipenem, indium In-111 pentetreol, indobufen, indol-3-ylacetic acid, indolebutyric acid, indometacin, invicorp, iocetamic acid, iodamidelodoxamic acid, ioglicic acid, iopanoic acid, iotalamic acid, iotroxic acid, ioxaglic acid, ioxitalamic acid, ipodic acid, isotretinoin, karetazan, alpha-ketoglutaric acid, ketoprofen, ketorolac, lactobionic acid, lasalocid A, latamoxef, letosteine, levo carnitine acetate, levocabastine, levocetirizine, levofloxacin, levofolinic acid, levomefolic acid, levopropicillin, levothyroxine, limaprost, liothyronine, liraglutide, lisinopril, lobenzarit, lodoxamide, lomefloxacin, lonazolac, lonidamine, loracarbef, loxoprofen, lubiprostone, lumiracoxib, luprostiol, lusupultide, lymecycline, marbofloxacin, mecillinam, meclofenamic acid, mecoprop-P, mefenamic acid, mefenpyr-diethyl, mefolinate, meglutol, meloxicam, melphalan, mepifylline, meropenem, mesalazine, metadoxine, metampicillin, methotrexate, methyldopa, metiazinic acid, meticillin, metirosine, metsulfuron, mezlocillin, midoriamin, miloxacin, mitiglinide, moexipril, mofezolac, monensin, montelukast, moxifloxacin, mupirocin, mycophenolic acid, nadifloxacin, nadroparin, nafcillin, nalidixic acid, naphthalene-1-acetic acid, naproxen, naptalam, narasin, natamycin, nateglinide, nedocromil, nesiritide, nicotinic acid, niflumic acid, nisin, norfloxacin, N-phenylphthalamic acid, nystatin, ofloxacin, olopatadine, olsalazine, orazamide, orbifloxacin, orotic acid, oxaceprol, oxacillin, oxaprozin, oxitriptan, oxolinic acid, ozagrel, pamoic acid, panipenem, pantothenic acid, parahydroxycinnamic acid, pasiniazid, pazufloxacin, pefloxacin, peforelin, pelargonic acid, pemetrexed, penicillin G, peramivir, perindopril, phenethicillin, phenoxymethylpenicillin, photofrin, phthalylsulfathiazole, picloram, pidolic acid, pidotimod, pipemidic acid, piperacillin, pirenoxine, piretanide, piromidic acid, piroxicam, pirprofen, pivagabine, pralatrexate, pranoprofen, pregabalin, primisulfuron-methyl, probenecid, procodazole, proglumide, prohexadione, propagermanium, propicillin, protizinic acid, prulifloxacin, pyrazosulfuron, pyrithiobac, quinapril, quinaprilat, quinclorac, quinmerac, quizalofop, quizalofop-P, raltitrexed, ramatroban, ramipril, ranelic acid, rebamipide, repaglinide, rhodamine B, ritiometan, robenacoxib, romurtide, rosoxacin, rotraxate, (R)-trolox, rufloxacin, salicylic acid, salinomycin, salsalate, sarafloxacin, sarpogrelate, semax, semduramicin, seratrodast, sincalide, sivelestat, sofalcone, somatorelin, somatostatin, sorbic acid, spaglumic acid, sparfloxacin, spirapril, stepronin, stibogluconic acid, (S)-trolox, sugammadex, sulbactam, sulbenicillin, sulfasalazine, sulfasuccinamide, sulfometuron, sulfosate, sulindac, suprofen, suxibuzone, talaporfin, tamibarotene, tazobactam, tecloftalam, teicoplanin, telmesteine, telmisartan, temocapril, temocillin, tenoic acid, teriparatide, tetracosactide, thioctic acid, thiomersal, thymalfasin, tiagabine, tianeptine, tiaprofenic acid, tiaprost, ticarcillin, tidiacic, timonacic, tiopronin, tiratricol, tirofiban, tocamphyl, tolfenamic acid, tolmetin, tolylphthalamic acid, tosufloxacin, trafermin, trandolapril, tranexamic acid, tranilast, trepibutone, treprostinil, tretinoin, tribenuron, triclopyr, tridecactide, triflusal, triflusulfuron, trolox, tropesin, trovafloxacin, ubenimex, undecylenic acid, ursodeoxycholic acid, valerenic acid, valproic acid, valsartan, vancomycin, vebufloxacin, vedaprofen, verteporfin, vigabatrin, zaltoprofen, zanamivir, ziconotide, zofenopril.

(88) Many of these active ingredients have a bitter or unpleasant taste.

(89) If desired, the active ingredients can also be used in the form of their pharmaceutically acceptable modifications or derivatives, and in the case of chiral active ingredients it is possible to use either optically active isomers or racemates or diastereoisomer mixtures. If desired, the compositions according to the invention can also comprise two or more pharmaceutical active ingredients.

(90) According to the invention, the coating compositions for the coating of cores comprising acidic active ingredients can be used in the form of extrudates, minitablets, granules, pellets, micropellets or crystals. The cores can also consist of nonpareils which have been coated with the acidic active ingredient.

(91) To produce dosage forms, the coated active-ingredient-containing cores can be mixed with suitable auxiliaries and compacted to give tablets which disintegrate in the aqueous environment of the oral cavity and release the coated fine shaped articles. Of particular importance here are the so-called oral dispersibles, i.e. tablets which disintegrate in the mouth within a short time and release the small shaped articles provided with the coatings according to the invention.

(92) Furthermore, the coating compositions can also advantageously be used for coating tablets.

(93) The excellent taste masking results from the insolubility of the polymers according to the invention at pHs above 6 and the rapid solubility at pHs below 6. I.e., in the saliva (pH: 7.2) correspondingly coated forms are stable for a very long time and there is no contact of the bitter pharmaceutical with the oral mucosa, but in the stomach at pHs of 1 to 5, a very rapid release of the active ingredient takes place. Dissolution is then so rapid that there is no difference in the onset of action compared with an uncoated form. As a rule, film coatings of a polymer according to the invention dissolve within min in gastric juice, whereas in phosphate buffer pH 7.2 they are stable over 2 hours. Surprisingly, the film coatings also dissolve relatively quickly in media with pHs of 4.5, meaning that the dosage forms produced therefrom develop a rapid action even in the case of an acidic patients or patients being treated with antacids.

(94) The coating compositions according to the invention have good stability against variation in release under thermal stress. In many cases, the stability against yellowing is also marked. Furthermore, the water vapor permeability is also advantageously influenced.

EXAMPLES

(95) Abbreviations Used

(96) BHT: butylhydroxybenzene NAC: N-acetylcysteine ATBC: acetyltributylcitrate TEC: triethylcitrate MEHQ: hydroquinone monomethylether d: days demin.: demineralized Ludipress®: formulated product of lactose (90%), povidone (3.5%) and crospovidone (3.5%) Avicel® PH 102: microcrystalline cellulose Kollidon® VA 64: vinylpyrrolidone—vinylacetate (6:4) copolymer (copovidone) Kollidon® CL: crosslinked polyvinylpyrrolidone (crospovidone) Kollicoat® IR: polyvinylalcohol—polyethylene glycol 6000 graft polymer (weight ratio PVA:PEG 75:25, degree of saponification 94 mol %), molecular weight: 45 000 Daltons

(97) All data in % relate to % by weight, unless stated otherwise.

(98) Cationic Polymers:

(99) The preparation of the polymers takes place analogously to Example 1 in WO 2009/016258. Polymer A: methylmethacrylate/diethylaminoethylmethacrylate, weight ratio 60:40, Polymer B: methylmethacrylate/diethylaminoethylmethacrylate, weight ratio 55:45 Polymer C: methylmethacrylate/diethylaminoethylmethacrylate, weight ratio 53:47

(100) The K values measured at 0.1 strength by weight in NMP were 50+/−0.5

(101) The polymers were used as 30% strength by weight aqueous dispersions with a pH of 9+/−0.3. The average particle size of the primary dispersion was 110 nm.

(102) The determination of the release from administration forms was carried out using the instrument with paddle stirrer described in the Pharmacopoeia of the USA (USP 32) under Dissolution.

Example 1

(103) Coated Acetylsalicylic Acid Tablet 100 mg

(104) Formulation of the Tablet:

(105) TABLE-US-00001 Ludipress 189 mg Avicel PH 101 40 mg Acetylsalicylic acid 100 mg Stearic acid 1 mg Tablet weight 330 mg Method direct tabletting Tablet shape convex Diameter 9 mm
Spray Formulation for Inner Layer:

(106) TABLE-US-00002 Kollicoat IR 12% Talc  8% Demin. Water 80% Solids content 20%
Coating Conditions:

(107) TABLE-US-00003 Machine Accela Cota 24/ horizontal drum coater Inlet air temperature 55° C. Spraying pressure 2.5 bar Shaping air pressure 1 bar Spray die Schlick 930/1 mm Air supply rate 200 m.sup.3/h Charge 7 kg Spraying rate 30 g/min Application rate 1.5 mg/cm.sup.2
Spray Formulation for Outer Layer:

(108) TABLE-US-00004 Polymer B (30% strength dis- 33.33% persion) Tributylcitrate  1.50% Butylhydroxytoluene 0.5   Talc 6%   Titanium dioxide 2%   Demin. water 56.67% Solids content 20%  
Coating Conditions:

(109) TABLE-US-00005 Machine Accela Cota 24/ horizontal drum coater Inlet air temperature 55° C. Spraying pressure 2 bar Shaping air pressure 1 bar Spray die Schlick 930/1 mm Air supply rate 200 m.sup.3/h Charge 7 kg Spraying rate 30 g/min Application rate 4.5 mg/cm.sup.2
Result:
Release in Acetate Buffer pH 4.5

(110) TABLE-US-00006 Time 3 months 3 months in Starting value 30/70% r.h. 40° C. min in % in % in % 15 73.5 74.6 73.9 30 99.8 98.9 99.5 60 100.2 100.3 99.7
Release in Phosphate Buffer pH 6.8

(111) TABLE-US-00007 Time 3 months 3 months in Starting value 30/70% r.h. 40° C. min in % in % in % 15 0.2 0.3 0.4 30 0.3 0.3 0.3 60 0.4 0.5 0.6
Further Properties

(112) TABLE-US-00008 3 months 3 months Starting value 30/70% r.h. 40° C. Appearance Smooth, shiny, Smooth, shiny, Smooth, shiny, no adhesion, no adhesion, no adhesion, no damage no damage no damage Taste test No bitter taste No bitter taste No bitter taste after 5 min in after 5 min in after 5 min in the mouth the mouth the mouth

Comparative Example to 1

(113) Preparation Analogous to Example 1 but without the Inner Layer

(114) Release in Acetate Buffer pH 4.5

(115) TABLE-US-00009 Time 3 months 3 Months in Starting value 30/70% r.h. 40° C. min in % in % in % 15 72.5 81.5 89.7 30 99.6 98.5 99.1 60 99.8 100.3 99.9
Release in Phosphate Buffer pH 6.8

(116) TABLE-US-00010 Time 3 months 3 months in Starting value 30/70% r.h. 40° C. min in % in % in % 15 0.4 12.3 10.6 30 1.8 25.7 23.4 60 3.9 54.8 49.8
Further Properties

(117) TABLE-US-00011 3 months 3 months Starting value 30/70% r.h. 40° C. Appearance Smooth, shiny, Rough, matt, Rough, matt, no adhesion, tablets stick, tablets stick, no damage significant significant damage damage Taste test No bitter taste Bitter taste Bitter taste after 5 min in after 0.5 min after 0.5 min the mouth in the mouth in the mouth

Example 2

(118) Coated Ibuprofen Tablet 200 mg

(119) Formulation of the Tablet:

(120) TABLE-US-00012 Ibuprofen 200 mg Avicel PH 101 142.5 mg Kollidon CL 10 Aerosil 200  6 Magnesium stearate 1.5 mg Tablet weight 360 mg Method Direct tabletting Tablet shape convex Diameter 9 mm
Spray Formulation for Inner Layer:

(121) TABLE-US-00013 Kollicoat IR 12% Talc  8% Demin. water 80% Solids content 20%
Coating Conditions:

(122) TABLE-US-00014 Machine Accela Cota 24/ horizontal drum coater Inlet air temperature 55° C. Spraying pressure 2.5 bar Shaping air pressure 1 bar Spray die Schlick 930/1 mm Air supply rate 200 m.sup.3/h Charge 7 kg Spraying rate 30 g/min Application rate 1.5 mg/cm.sup.2
Spray Formulation for Outer Layer:

(123) TABLE-US-00015 Polymer A (30% strength dis- 33.33% persion) Acetyltriethyl citrate  1.50% Butylhydroxytoluene 0.5   Talc 6%   Titanium dioxide 2%   Demin. water 56.67% Solids content 20%  
Coating Conditions:

(124) TABLE-US-00016 Machine Accela Cota 24/ horizontal drum coater Inlet air temperature 55° C. Spraying pressure 2 bar Shaping air pressure 1 bar Spray die Schlick 930/1 mm Air supply rate 200 m.sup.3/h Charge 7 kg Spraying rate 30 g/min Application rate 4.5 mg/cm.sup.2
Result:
Release in Acetate Buffer pH 4.5

(125) TABLE-US-00017 Time 3 months 3 months in Starting value 30/70% r.h. 40° C. min in % in % in % 15 43.4 44.6 42.9 30 81.8 82.6 80.5 60 98.9 99.9 99.2
Release in Phosphate Buffer pH 6.8

(126) TABLE-US-00018 Time 3 months 3 months in Starting value 30/70% r.h. 40° C. min in % in % in % 15 0.1 0.2 0.4 30 0.3 0.5 0.5 60 0.5 0.7 0.5
Further Properties

(127) TABLE-US-00019 3 months 3 months Starting value 30/70% r.h. 40° C. Appearance Smooth, shiny, Smooth, shiny, Smooth, shiny, no adhesion, no adhesion, no adhesion, no damage no damage no damage Taste test No bitter taste No bitter taste No bitter taste after 5 min in after 5 min in after 5 min in the mouth the mouth the mouth

Example 3

(128) Coated Ibuprofen Minipellets

(129) Composition of the Pellets

(130) TABLE-US-00020 Composition per pellet Substance [%] Ibuprofen 100 Pellet size 200 to 400 μm
Composition of the Spray Formulation
Spray Formulation for Inner Layer:

(131) TABLE-US-00021 Kollicoat IR 12% Talc  8% Demin. water 80% Solids content 20%
Coating Parameters

(132) Coating was carried out in a fluidized-bed granulator “Glatt GPCG 3.1” from Glatt.

(133) TABLE-US-00022 Spray nozzle 1 mm diameter Number of spray nozzles 1 Filling 2.5 kg of ibuprofen pellets 200-400 μm Method Bottom-Spray (Wurster) Spraying pressure 2.0 bar Inlet air temperature 55° C. Outlet air temperature 39° C. Spraying rate 15 g/min Drying ca. 5 min Application rate/weight increase 5%
Spray Formulation for Outer Layer:

(134) TABLE-US-00023 Polymer B (30% dispersion) 33.33% Triethylcitrate  1.50% Yellow iron oxide 0.5   Talc 6%   Titanium dioxide 2%   Demin. Water 56.67% Solids content 20%  
Coating Parameters

(135) Coating was carried out in a fluidized-bed granulator “Glatt GPCG 3.1” from Glatt.

(136) TABLE-US-00024 Spray nozzle 1 mm diameter Number of spray nozzles 1 Filling 2.5 kg of ibuprofen pellets 200-400 μm Method Bottom-Spray (Wurster) Spraying pressure 1.0 bar Inlet air temperature 45° C. Outlet air temperature 29° C. Spraying rate 15 g/min Drying ca. 5 min Application rate/weight increase 20%

(137) After the coating, the pellets were mixed with 0.2% Aerosil 200 for 10 min in a Turbula mixer.

(138) Result:

(139) Release in Acetate Buffer pH 4.5

(140) TABLE-US-00025 Time 3 months 3 months in Starting value 30/70% r.h. 40° C. min in % in % in % 15 58.2 60.0 58.1 30 89.5 91.2 90.5 60 99.7 99.9 99.2
Release in Phosphate Buffer pH 6.8

(141) TABLE-US-00026 Time 3 months 3 months in Starting value 30/70% r.h. 40° C. min in % in % in % 15 0.8 0.9 1.1 30 1.5 1.9 1.6 60 2.6 2.8 2.9
Further Properties

(142) TABLE-US-00027 3 months 3 months Starting value 30/70% r.h. 40° C. Appearance Smooth, no Smooth, no Smooth, no adhesion, no adhesion, no adhesion, no damage damage damage Taste test No bitter taste No bitter taste No bitter taste after 5 min in after 5 min in after 5 min in the mouth the mouth the mouth

Example 4

(143) Coated Ketoprofen Pellets

(144) Formulation of the Pellets:

(145) TABLE-US-00028 Ketoprofen 20% Avicel PH 101 40% Granulac 230 40% Method Extrusion, spheronization Pellet diameter 0.7-1.4 mm
Composition of the Spray Formulation
Spray Formulation Inner Layer:

(146) TABLE-US-00029 Kollicoat Protect 12% Talc  8% Demin. Water 80% Solids content 20%
Coating Conditions for the Inner Layer:

(147) TABLE-US-00030 Machine Aeromatic Strea/ Wurster insert Inlet air temperature 60° C. Spraying pressure 2.0 bar Nozzle diameter 0.8 mm Air supply rate 85-100 m.sup.3 Charge 0.5 kg Spraying rate 8 g/min Application rate 1.0 mg/cm.sup.2
Spray Formulation for Outer Layer:

(148) TABLE-US-00031 Polymer C (30% strength dis- 33.33% persion) Tributylcitrate  1.50% Sunset Yellow AI lake 0.5   Talc 6%   Titanium dioxide 2%   Demin. water 56.67% Solids content 20%  
Coating Conditions for the Outer Layer:

(149) TABLE-US-00032 Machine Aeromatic Strea/ Wurster insert Inlet air temperature 52° C. Spraying pressure 1.3 bar Nozzle diameter 0.8 mm Air supply rate 85-100 m.sup.3 Charge 0.5 kg Spraying rate 8 g/min Application rate 4.5 mg/cm.sup.2

(150) After the coating, the pellets were mixed with 0.2% Aerosil 200 for 10 min in a Turbula mixer.

(151) Result:

(152) Release in Acetate Buffer pH 4.5

(153) TABLE-US-00033 Time 3 months 3 months in Starting value 30/70% r.h. 40° C. min in % in % in % 15 41.2 39.9 40.5 30 75.4 74.5 76.6 60 98.6 97.7 99.5
Release in Phosphate Buffer pH 6.8

(154) TABLE-US-00034 Time 3 months 3 months in Starting value 30/70% r.h. 40° C. min in % in % in % 15 0.8 0.9 0.6 30 1.3 1.2 1.1 60 1.8 2.0 1.5
Further Properties

(155) TABLE-US-00035 3 months 3 months Starting value 30/70% r.h. 40° C. Appearance Smooth, no Smooth, no Smooth, no adhesion, no adhesion, no adhesion, no damage damage damage Taste test No bitter taste No bitter taste No bitter taste after 5 min in after 5 min in after 5 min in the mouth the mouth the mouth