(12) Patent Application Publication (10) Pub. No.: US 2003/0060381A1 Meier Et Al

US 2003OO60381A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2003/0060381A1 Meier et al. (43) Pub. Date: Mar. 27, 2003

(54) DISPERSION COMPRISING A NON-IONIC (30) Foreign Application Priority Data EMULSIFIER Mar. 10, 2000 (DE)...... 100 11447.4 (76) Inventors: Christian Meier, Darmstadt (DE); Johanna Eisele, Darmstadt (DE); Publication Classification Michael Schnabel, Biebesheim (DE); Klaus Schultes, Wiesbaden (DE); (51) Int. Cl." ...... A61K 7/50 Stefan Grimm, Worms (DE); (52) U.S. Cl...... 510/141; 510/153 Hans-Ulrich Petereit, Darmstadt (DE); Thomas Suefke, Erzhausen (DE) (57) ABSTRACT Correspondence Address: The invention relates to a dispersion Suitable for use as OBLON, SPIVAK, MCCLELLAND, MAIER & coating agent and binder for pharmaceutical forms, having NEUSTADT, P.C. a solids content of 10-70% by weight consisting of 1940 DUKE STREET a) from 90 to 99% by weight of a methacrylate copolymer ALEXANDRIA, VA 22314 (US) consisting of at least 90% by weight of (meth)acrylate monomers containing neutral radicals and having a (21) Appl. No.: 09/926,484 glass transition temperature Tg of from -20°C. to +20 C. as determined by the DSC method, and (22) PCT Filed: Feb. 2, 2001 b) 1-10% by weight of a nonionic emulsifier having an (86) PCT No.: PCT/EP01/01108 HLB of from 15.2 to 17.3. Patent Application Publication Mar. 27, 2003. Sheet 1 of 2 US 2003/0060381 A1

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DISPERSION COMPRISING ANON-ONC or no fractions of monomers containing ionic radicals in EMULSIFIER Such a way that, while retaining the Stability of the disper 0001. The invention relates to the field of dispersions and Sion and its particle size distribution, it is possible to use it to their use as coating agents and binders for pharmaceutical to prepare medicament formulations in which phase Sepa forms. ration with the formation of crystal Structures as a result of the emulsifier does not occur. At the same time, there should PRIOR ART be no deleterious alteration to the active Substance release characteristics and other properties-mechanical properties, 0002 The use of so-called neutral methacrylate copoly for example. mers, i.e. methacrylate copolymers consisting predomi nantly of (meth)acrylate monomers with neutral radicals, 0010 This problem has been solved by means of a Such as methyl methacrylate or ethyl methacrylate as coating dispersion Suitable for use as a coating agent and binder for agents and binders for pharmaceutical forms with delayed pharmaceutical forms, having a solids content of 10-70% by active-Substance release has been known for a long time. weight consisting of 0.003 Uses in mixtures with anionic dispersions are 0011) a) from 90 to 99% by weight of a methacrylate described, for example, in EP-A 152038, EP-A 208 213 or copolymer consisting of at least 90% by weight of EPA 617 972. (meth)acrylate monomers containing neutral radicals and having a glass transition temperature Tg of from 0004. The neutral methacrylate copolymers are nowa –25° C. to +20° C. as determined by the DSC method days used preferably as dispersions. Dispersions of this kind (ISO 11357), and are prepared by emulsion polymerization and therefore include as a result of their preparation an emulsifier, which 0012 b) 1-10% by weight of a nonionic emulsifier also brings about the Stability of the resulting dispersion per having an HLB of from 15.7 to 16.2. Se. In the finished pharmaceutical form, moreover, the 0013) Implementation of the Invention emulsifier present influences the active Substance release 0014) Methacrylate Copolymer characteristics. 0.015 The dispersion of the invention comprises 90-99% 0005. As a result of the intended use in pharmaceuticals, by weight, based on the Solids content, of a methacrylate and on account of the fact that owing to the monomer copolymer. composition the copolymers have few if any charges, the 0016. The methacrylate copolymer consists of at least 90, Selection of appropriate emulsifiers is very limited. in particular 95, preferably 97, in particular 99, with par 0006 Göferich and Lee in “The influence of endogenous ticular preference 100% by weight of (meth)acrylate mono Surfactant On the Structure and drug-release properties of mers containing neutral radicals, especially C to C alkyl Eudragit NE30D matrices”, Journal of Controlled Release radicals. 18 (1992), pp. 133-144, describe how an emulsifier of the 0017 Examples of Suitable monomers are methyl meth nonylphenol type present in the dispersion causes problems acrylate, ethyl methacrylate, butyl methacrylate, methyl for the release of active Substance from coated pharmaceu acrylate, ethyl acrylate and butyl acrylate. Preference is tical forms. The authors describe an anisotropic Structure in given to methyl methacrylate, ethyl acrylate and methyl copolymer films obtained from the dispersion. Both in films acrylate. containing active Substance and in films free of active Substance, phase Separation and crystallization of the emul 0018. In small fractions, not more than 10, preferably not sifier occur as a function of the Storage period and the active more than 5, with particular preference not more than 3 or Substance content. These occurrences obviously result in not more than 1% by weight, methacrylate monomers con inconsistencies in the release of the active Substance clen taining anionic radicals, e.g. methacrylic acid, may be buterol. If the emulsifier is removed from freeze-dried present. copolymer by Washing with water, then a uniform-al 0019. The methacrylate copolymer has a glass transition though slowed-release of active Substance is observed in the purified copolymer. temperature Tg of from -25 C. to +20 C., preferably from -10° C. to 0° C., determined by the DSC method (ISO 0007 DE-A 19503 099 describes a process for preparing 11357). aqueous addition-polymer dispersions by the method of 0020. A typical methacrylate copolymer may be com free-radical aqueous emulsion polymerization in the pres posed, for example, of 25-35% by weight methyl methacry ence of a nonionic emulsifier. Suitable nonionic emulsifiers late and from 75 to 65% by weight ethyl acrylate. are those whose cloud point is situated below the polymer ization temperature. A large number of Suitable compounds 0021. In accordance with the invention, the polymers is listed, including nonylphenol emulsifiers. which are neutral per Se-may include Small amounts of methacrylic acid, which although causing virtually no alter 0008 Problem and Solution ation in the water-insolubility of the polymer may never 0009. The problem was seen to be to improve prior art theless influence Swelling and permit pH-dependent control dispersions comprising methacrylate copolymers with Small of the permeability. US 2003/0060381 A1 Mar. 27, 2003

0022. Emulsifiers 0032) Preparation of the Dispersion 0023 The dispersion of the invention contains from 1 to 0033. The novel dispersion is obtained in a manner 10, preferably from 2 to 8, with particular preference from known per se by aqueous emulsion polymerization by the 4 to 6% by weight, based on the Solids content, of a nonionic batch technique or the feed technique, Semi-continuously or emulsifier having an HLB of from 15.7 to 16.2. else continuously (in this respect See, for example, DE 195 0024. Emulsifiers control the course of the emulsion 03 099 A1). polymerization proceSS by permitting the chain-building 0034. The free-radical polymerization of the monomers reaction of the emulsified monomers in the water phase. in the presence of the emulsifier takes place by means of They therefore constitute an auxiliary which is necessary for radical-forming water-Soluble polymerization initiators, it the preparation and which determines the properties of the being possible for radical formation to take place thermally dispersion. They cannot normally be replaced without fun or by way of redox processes. If desired, molecular weight damental changes in relevant properties of the dispersion. regulators are added for the purpose of adjusting the molar 0025. The HLB, introduced by Griffin in 1950, is a masses. Emulsion polymers are commonly prepared in measure of the hydrophilicity of lipophilicity of nonionic concentrations between 10 and 70% by weight. A solids Surfactants. It may be determined experimentally by the content of 30-50% by weight is advantageous. Batchwise phenol titration method of Marszall; cf. "Parfimerie, Kos preparation generally takes place in Stirred tank reactors. metik”, Volume 60, 1979, pp. 444-448; further literature 0035. For the preparation, in the case of a simple batch references are in Römpp, Chemie-Lexikon, 8th ed. 1983, p. preparation, all monomers are charged to a reaction vessel in 1750. See also, for example, U.S. Pat. No. 4,795,643 (Seth). accordance with the desired copolymer composition, 0026. An HLB (hydrophilic/lipophilic balance) can be together with the emulsifier, initiators, regulators and other determined exactly only for nonionic emulsifiers. For auxiliaries and together with water, and are dissolved or anionic emulsifiers, this value may be determined arithmeti dispersed therein. By activating the initiator (increasing the cally but is virtually always above or well above 20. temperature, adding the redox agent), the polymeric chain reaction is initiated and conducted. In the course of this 0027. The HLB values in emulsifiers have a distinct reaction, the known lateX particles, consisting of polymer influence on the crystallization of the emulsifier. Ideally chains, are formed. these values are between 15.7 and 16.2. Above the claimed range, the emulsifiers crystallize out after drying. Emulsifi 0036) Antifoam emulsion and stabilizers may be added to erS having an HLB below the claimed range are unable to the dispersion. stabilize the dispersion sufficiently, which is evident from 0037 Uses severe coagulation. The HLB values were either taken from the literature (Fiedler: Lexikon der Hilfsstoffe) or calculated 0038. The novel coating agents may be processed corre in accordance with W. C. Griffin (supplement from Parfim spondingly like other known aqueous, acrylate-based coat erie and Kosmetik 64, 311-314, 316 (1983); Hithig Verlag, ing agents. The most common coatings are coatings on Heidelberg/Pharm. Ind. 60 No. 1 (1998); dielectricity ther particles with a size of from 0.1 to 3 mm by the fluid-bed moanalysis). coating process. Customary additions, Such as pigments, fillers, thickeners, defoamers, preservatives, etc., may be 0028. The emulsifier is to be toxicologically unobjection used in customary amounts. Coatings may be produced on able, and therefore nonionic emulsifiers are preferred. plain tablets, capsules, film-coated tablets, granules or crys 0029 Suitable emulsifier classes are ethoxylated fatty tals. The formation of matrix tablets or matrix granules is acid esters or ethers, ethoxylated Sorbitan ethers, ethoxylated also possible. Preferred processing temperatures are situated alkylphenols, glycerol esters or Sugar esters, or wax deriva within the range from 20 to 40 C. Suitable film thicknesses tives. are from 10 to 80 micrometers. 0030) Suitable emulsifiers are, for example, polyoxyeth 0039. By means of the coating film, the mechanism of ylene-glycerol monolaurate, polyoxyethyleneglycerol active Substance release by diffusion may be utilized not monoStearate, polyoxyethylene-20-cetyl Stearate, polyoxy only in the gastrointestinal tract but also in other body ethylene-25-cetyl Stearate, polyoxyethylene(25)-oxypropy cavities, tissues, blood circulations and the habitats of ani lene monoStearate, polyoxyethylene-20-Sorbitan mono mals and plants for the purpose there of inducing delayed palmitate, polyoxyethylene-16-tert-octylphenol, release of active Substances. Examples are films which are polyoxyethylene-20-cetyl ether, polyethylene glycol(1000) introduced into the blood circulation using catheters, and monocetyl ether, ethoxylated castor oil, polyoxyethylene implants of Veterinary pharmaceuticals. Sorbitol-lanolin derivatives, polyoxyethylene(25)propylene 0040 AS with other aqueous coating agents, coats of glycol Stearate and polyoxyethyleneSorbitol esters. multi-layer coating Systems may be produced. For example, 0.031 Preference is given to polyoxyethylene-25-cetyl a core containing, for example, basic or water-Sensitive Stearate, polyoxyethylene-20-Sorbitan monopalmitate, poly active Substances may be provided with an insulating coat of oxyethylene-16-tert-octylphenol and polyoxyethylene-20 another coating material, Such as cellulose ether, cellulose cetyl ether. ester, cationic polymethacrylates (such as EUDRAGIT(R) US 2003/0060381 A1 Mar. 27, 2003

E100, -RL 100, RS 100, Röhm GmbH) before the coating 0057 Use of the Solid: agent of the invention is applied. Likewise, further coatings, 0.058. The solid obtained from the dispersions of the with for example an odour-masking or paste-concealing invention by drying, coagulation or pinch-off extrusion may effect or with an appealing colour or gloSS effect, may be applied Subsequently. be used as follows: 0059 Extrusion: after blending with auxiliaries and/or 0041. The release characteristics of pharmaceutical coat active Substances, if desired, to give granules, films and the ings in vitro are tested in accordance with USP normally like. with artificial gastric fluid (0.1NHCl) and artificial intestinal fluid (pH 6.8). 0060 Injection moulding: in accordance with the new injection moulding application, to give hollow articles and 0.042 Further applications are described in the following monolithic carriers. literature: 0061 Dissolution: the polymer is soluble in customary 0043 Bauer, Lehmann, Osterwald, Rothgang: Coated Solvents Such as short-chain alcohols or ketones. Such Dosage Forms, CRC Press LLC, Boca Raton, Fla., Solutions may be employed in customary coating processes. Medpharm Scientific Publishers, Suttgart 1998 0044 I. Ghebre-Sellassie, Multiparticulate Oral Drug 0062) Advantageous Effects of the Invention Delivery, Marcel Dekker, Inc. New York, Basle, Hong 0063. The dispersions of the invention are used as coating Kong, 1994 agents and binders in the production of medicaments. Pri marily, therefore, it is necessary to achieve the physico 0.045 Spray Applications of Mixtures with Other Disper chemical properties necessary for this effect (see example 4 Sions: and 5). Particularly advantageous in this context is reliable 0046 K. Lehmann, D. Dreher: Mixtures of Aqueous filming at temperatures below 10° C., thereby enabling Polymethacrylate Dispersions for Drug Coating, Drugs processing without the addition of plasticizer. The repro made in Germany 31 101-102 (1988) ducible coalescence of the lateX particles permits the for 0047. Matrix Tablets by Wet Granulation mulation of delayed-release pharmaceutical forms. 0048 K. Lehmann, H.-U. Petereit, Verwendung wari 0064. If the above-described crystallization of emulsifiers ger Poly(meth)acrylat-Dispersionen für die Herstellung occurs, it constitutes a considerable reduction in the quality of medicaments. For the purposes of medicament Safety, von Matrixtabletten Use of aqueous poly(meth)acry therefore, the crystallization of the emulsifiers after drying late dispersions for producing matrix tablets, Acta should be prevented. This effect is obviously achieved by Pharm. Technol. 34(4) 189-195 (1988) structural interaction of the emulsifier with the polymer. The 0049. J. McGinity, Aqueous Polymeric Coatings for dispersions of the invention therefore permit the develop Pharmaceutical Dosage Forms, 2nd Edition, Marcel ment of more reliable delayed-release pharmaceutical forms. Dekker, Inc. New York, Basle, Hong Kong, 1996 0065. The invention is suitable in particular for the pro 0050 Disintegrating Delayed-Release Tablets Vision of pharmaceutical forms comprising the active Sub 0051 K. Lehmann, H.-U. Petereit, D. Dreher, stances given below. Schnellzer-fallende Tabletten mit gesteuerter Wirkstof 0066. Therapeutic Categories: fabgabe Fast-disintegrating tablets with controlled 0067 Analgesics, antirheumatics, antiallergics, anti-ar active substance release), Pharm. Ind. 55, (10) 940-947 rhythmics, beta receptor blockers, calcium channel blockers, (1993) inhibitors of the renin-angiotensin System, broncholyticS/ 0.052 K. Lehmann, H.-U. Petereit, D. Dreher, Fast antasthmatics, cholinergics, diuretics, circulation promoters, Disintegrating Controlled Release Tablets from Coated gout agents, influenza agents, coronary agents, lipid reduc Particles, Drugs Made in Germany 37(2), 53–60(1994) ers, gastrointestinal agents, psychopharmaceuticals, platelet R. Bodmeier, Tabletting of Coated Pellets Eur. J. Phar aggregation inhibitors, urological agents, venous therapeutic and Biopharm. 431-8(1997) agents, Vitamins and minerals. 0053 (Trans) Dermal Therapy Systems 0068 Active substances 0054 Heilmann, K.: Therapeutische Systeme, Ferdi 0069 Morphine and its derivatives, tramadol, acetylsali nand Euler Verlag, Stuttgart, pp. 52-57. cylic acid, diclofenac, indomethacin, lonazolac, ibuprofen, ketoprofen, propyphenaZone, naproxen, paracetamol, flur 0.055 Brandau, R. and Lippold, B. H. (1982): Dermal biprofen, dimetindene, quinidine, metoprolol, propanolol, and Transdermal Absorption. Wissenschaftliche Ver oXprenolol, pindolol, atenolol, metoprolol, disopyramide, lags-gesellschaft mbH, Stuttgart, pp. 171-200. Verapamil, diltiazem, gallopamil, nifedipine, nicardipine, 0056 H.-U. Petereit, 3rd European Congress of Biop nisoldipine, nimodipine, amlodipine, theophylline, Salbuta harmaceutics and Pharmacokinetics-Proceed. Vol. I, mol, terbutaline, ambroXol, aminophylline, choline theo 84-93 (1987) phyllinate, pyridostigmine, piretanide, furosemide, pentoxi US 2003/0060381 A1 Mar. 27, 2003 fylline, naftidrofuryl, buflomedil, Xanthinol nicotinate, 0078 1-5. Variation of the Polymer Composition bencyclane, allopurinol, norephedrine, chlorphenamine, isosorbide mononitrate, isosorbide dinitrate, glycerol trini 0079. To prepare the dispersion, a reaction vessel is trate, molsidomine, beZafibrate, fenofibrate, gemfibrozil, charged with 55.0 kg of water and 328 g of polyoxyethylene cerivastatin, pravastatin, fluvastatin, lovastatin, atorvastatin, 20-cetyl ether are dissolved therein. Following dissolution, Simvastatin, Xanthinol, methoclopramide, amitriptyline, the monomers as per table 1, 6.6 kg of ethyl acrylate, 7.1 kg dibenzepine, Venla-faxine, thioridazine, oxazepam, lithium, of methyl methacrylate and 0.3 kg of methacrylic acid are nitro-furantoin, dry plant extract, ascorbic acid and potas added and the mixture is emulsified at 30° C. sium and the Salts thereof used pharmaceutically. EXAMPLES 0080. To start the reaction, the water-soluble initiators are added (0.22 g of iron(II) sulphate in solution in 160 g of 0070 Investigation Methods: water, 22.0 g of ammonium peroxodisulphate and 30.8 g of 0071 Solids content: 1 g of dispersion is dried in an oven Sodium disulphate, each in Solution in 320 g of water). After at 110° C. for 3 hours in accordance with Pharm. Eur, 2.2.32 the temperature peak has been reached, the batch is cooled. method d. At about 50 C., 754 g of emulsifier as in the table are added 0.072 pH: Determined in accordance with Pharm. Eur. for subsequent stabilization. After 40 C. has been reached, Method 2.2.3. 6.7 g of ammonium perOXOdisulphate in Solution in 160 g of 0.073 Dynamic viscosity: determined using a Brookfield water are added for the after-reaction and the dispersion is viscometer (UL adapter/30 min' C.) filtered and then deodorized.

Methyl Meth- Dynamic Crystal Ethyl methacrylic Solids vis- Particle lization acrylate acrylate acid content cosity size of the Ex. part part part % pH mPas ris nm emulsifier

1. 70 3O O 30.6 2.7 SO 60.3 O 2 69 3O 1. 30.9 8.3 SO 76.O O 3 68 29 3 30.6 2.8 SO 57.5 O 4 66 29 5 3O.7 2.7 SO 618 O 5 63 27 1O 3O3 2.6 SO 89.0 O

0.074 Particle size: determined from dilute dispersion 0081 6-15. Variation of the Emulsifier using a Nanosizer (Coulter). 0082 To prepare the dispersion, a reaction vessel is 0075 Coagulum fraction: 100 g of dispersion are passed charged with 55.0 kg of water and 328 g of emulsifier in through a precision-weighed sieve with a mesh size of 0.09 accordance with the table are dissolved therein. Following mm (mesh number 90, ISO) and washed through with dissolution, 16.6 kg of ethyl acrylate, 7.1 kg of methyl purified water until the runnings are clear. Sieve and residue methacrylate and 0.3 kg of methacrylic acid are added and are dried to constant weight at 105 C. and weighed pre the mixture is emulsified at 30° C. To start the reaction, the cisely. The weight difference is calculated as a % of the water-soluble initiators are added (0.22g of iron(II) sulphate amount of dispersion investigated. in Solution in 160 g of water, 22.0 g of ammonium perOXO 0076) Crystallization of the Emulsifier: disulphate and 30.8g of Sodium disulphate, each in Solution in 320 g of water). After the temperature peak has been 0.077 About 0.3 g of dispersion is placed on a slide and reached, the batch is cooled. At about 50 C., 754 g of dried at <10 C. for at least 12 h. The crystallization of the emulsifier as in the table are added for Subsequent Stabili emulsifier in the dried film is Subsequently examined under zation. After 40 C. has been reached, 6.7 g of ammonium a polymerization microscope at 400-fold magnification. perOXOdisulphate in Solution in 160 g of water are added for Crystallization is evident from the coloured birefringences, the after-reaction and the dispersion is filtered and then amorphous regions appear dark. deodorized. US 2003/0060381 A1 Mar. 27, 2003

Solids Dynamic content viscosity Particle size Coagulum Crystallization of Ex. Emulsifiers HLB (%) PH mPa *s rNs (nm) content % the emulsifier 6 Polyoxyethylene-100- 19.1 50.4 2.5 68OO 81 <0.5 yes isononylphenol 7 polyoxyethylene-100-stearyl ether 18.8 50.6 2.4 760 88 n.d. yes 8 Polyoxyethylene-50-nonylphenol 18.3 50.2 2.7 1225 76 O.04 yes 9 Polyoxyethylene-35-nonylphenol 17.5 51.7 n.d. n.d. 72 O1 yes 10 Polyoxyethylene-25-cetyl stearate 16.2 48.7 2.6 200 77 O.2 O 11 Polyoxyethylene-20-sorbitan 16.O 45.5 2.7 n.d. 112 n.d. O monopalmitate 12 Polyoxyethylene-16-tert- 15.8 50.6 2.5 28OO 90 O.O6 O octylphenol 13 Polyoxyethylene-20-cetyl ether 15.7 50.5 2.5 350 14 Polyoxyethylene-20-sorbitan 15.6 n.d. n.d. n.d. n.b. >10 n.d. mOnOStearate 15 Polyoxyethylene-20-sorbitan 15.3 47.7 2.6 48O 91 8.21 n.d. monooleate n.d. *) not determinable, owing to coagulation

0083) 16-18. Variation of the Preparation Process disulphate in solution in 160 g of water) is added for the after-reaction. For deodorization, the dispersion is adjusted 0084 16. Dispersion Preparation by Emulsion Polymer to a pH of about 8 using dilute sodium hydroxide solution in ization by the Single-Stage Batch Process a reaction vessel, and 10-15% of the dispersion water are 0085 To prepare the dispersion, a reaction vessel is distilled off. Thereafter the dispersion is diluted to a solids charged with 55.0 kg of water and 328 g of polyoxyethylene content of approximately 30%. The dispersion thereafter is 20-cetyl ether in accordance with the table are dissolved filtered. therein. Following dissolution, 16.6 kg of ethyl acrylate, 7.1 kg of methyl methacrylate and 0.3 kg of methacrylic acid are 0091 18. Dispersion Preparation by Emulsion Polymer added and the mixture is emulsified at 30° C. ization by the Feed Process 0.086 To start the reaction, the water-soluble initiators are 0092. In a glass reactor, 2370 g of water and 5.0 g of added (0.22 g of iron(II) sulphate in solution in 160 g of emulsifier as per the table are heated to 80° C. with stirring. water, 22.0 g of ammonium perOXOdisulphate and 30.8 g of During this time, a preemulsion consisting of 1800 g of Sodium disulphate, each in Solution in 320 g of water). After water, 64.9 g of emulsifier, 3.0 g of ammonium peroxodis the temperature peak has been reached, the batch is cooled. ulphate, 1245.6 g of ethyl acrylate, 532.8 g of methyl At about 50 C., 754 g of emulsifier as in the table are added methacrylate and 21.6 g of methacrylic acid is prepared for Subsequent stabilization. After 40 C. has been reached, using a high-Shear Stirrer. The amount of initiator (1.2 g of 6.7 g of ammonium perOXOdisulphate in Solution in 160 g of ammonium peroxodisulphate in Solution in 30 g of water) water are added for the after-reaction and the dispersion is provided for the initiation of the reaction is added to the filtered and then deodorized. initial charge and the preemulsion is metered into the initial charge over the course of four hours at 80° C. After the end 0087. 17. Dispersion Preparation by Emulsion Polymer of the feed, the resulting dispersion is stirred at 80 C. for ization in a Dual Batch Process two hours more, then cooled to room temperature and 0088 For the 1st batch of the dispersion, a reaction vessel adjusted to a pH of approximately 8 using dilute Sodium is charged with 23.0 kg of water and 512 g of emulsifier in hydroxide solution, and 10-15% of the dispersion water are accordance with the table are dissolved therein. Following distilled off. The dispersion is subsequently diluted to a dissolution, 8.30 kg of ethyl acrylate, 3.55 kg of methyl solids content of about 30%. Thereafter, the dispersion is methacrylate and 0.14 kg of methacrylic acid are added and filtered. the mixture is emulsified at 30° C. 0093. The dispersions obtained were tested for the prop 0089. To start the reaction, the water-soluble initiators are erties stated in the table. The table lists the analytical values added (0.22 g of iron(II) Sulphate, 11.0 g of ammonium of the dispersions in accordance with the abovementioned peroxodisulphate and 15.4 g of Sodium disulphate, each in preparation conditions. Solution in 160 g of water). After the temperature peak has been reached, the batch is cooled to 50 C. 0090. For the 2nd batch, 570 g of emulsifier are added to Solids Dynamic Particle Crystallization the 1st batch and the mixture is stirred for 30 minutes. content viscosity size of the Subsequently, in analogy to the 1st batch, the same amount Dispersion % pH mPas ris Inm emulsifier of monomers is added, the batch is stirred for 10 minutes and 16 30.9 8.3 &10 76 O the initiators are added (11.0 g of ammonium peroxodisul 17 29.6 8.3 &10 78 O phate and 15.4 g of Sodium disulphite, each in Solution in 18 30.2 8.3 &10 90 O 160 g of water). After the end of the reaction, the batch is cooled to 40° C. and initiator (6.7 g of ammonium peroxo US 2003/0060381 A1 Mar. 27, 2003

0094) 19. Use of the Dispersion as Coating Agent: 3. Dispersion according to claim 1 or 2, characterized in that the nonionic emulsifier is Selected from the Substance 0.095 a) Coatings on Potassium Chloride Crystals. group of the ethoxylated fatty acid esters or ethers, ethoxy 0096) In a fluid-bed coating unit (GPCG1, GLATT) 800 lated Sorbitan ethers, ethoxylated alkyl-phenols, glycerol g of KCl crystals (0.3-0.8 mm) are coated with a spray esters or Sugar esters, or wax derivatives. suspension of 373.3 g of inventive dispersion from example 4. Dispersion according to one or more of claims 1 to 3, 12, 112 g of talc, 0.95 g of antifoam emulsion and 412 g of purified water. The air entry temperature is 30° C. and the characterized in that the nonionic emulsifier is Selected from spray pressure at the nozzle (diameter 1.2 mm) is 2.0 bar. the group consisting of polyoxyethyleneglycerol monolau The Spraying time is about 90 minutes. After drying at room rate, polyoxyethyleneglycerol monoStearate, polyoxyethyl temperature for 16 hours, uniform coated crystals are ene-20-cetyl Stearate, polyoxyethylene-25-cetyl Stearate, obtained. polyoxyethylene(25)oxypropylene monostearate, polyoxy ethylene-20-Sorbitan monopalmitate, polyoxyethylene-16 0097. The release of the potassium chloride crystals was tert-octylphenol, polyoxyethylene-20-cetyl ether, polyethyl measured over 6 hours in a paddle device at 100 rpm in 900 ene glycol(1000) monocetyl ether, ethoxylated castor oil, ml of water. The potassium chloride content was determined polyoxyethylene Sorbitol-lanolin derivatives, by potentiometry. polyoxyethylene(25)propylene glycol Stearate and polyoxy 0098. The release profile of the potassium chloride crys ethylenesorbitol esters, preferably polyoxyethylene-25-cetyl tals coated with the inventive dispersion indicates uniform Stearate, polyoxyethylene-20-Sorbitan monopalmitate, poly delayed release over 6 h (see FIG. 1/2). oxyethylene-16-tert-octylphenol and polyoxyethylene-20 0099. 20. Use of the Dispersion as Binder: cetyl ether. 5. Process for preparing a dispersion according to one or 0100 Matrix tablets are produced with a total mass of more of claims 1 to 4 in a manner known perse by emulsion 600 mg and a diprophylline content of 150 mg. For 1.2 kg polymerization. of matrix tablets, 300 g of diprophylline are mixed with 400 6. Use of a dispersion according to one or more of claims g of calcium hydrogenphosphate dihydrate (0.1-0.2 mm) in 1 to 4 as a coating agent or binder for the preparation of the STEPHAN UM 12 and the mixture is subsequently medicaments. wetted with the inventive dispersion from example 12. After drying at 40 C. for 6 h, the tablet composition is passed 7. Use according to claim 6, characterized in that the through a 1 mm Sieve, mixed with 12 g of magnesium coated or bound medicaments comprise one of the following Stearate and compressed on a KORSCH eccentric tabletting active Substances: morphine and its derivatives, tramadol, acetylsalicylic acid, diclofenac, indomethacin, lonazolac, preSS at 10 kN. The resulting tablets have a slight gloSS, ibuprofen, ketoprofen, propyphenaZone, naproxen, parac possess good mechanical Strength, and exhibit a uniform etamol, flurbiprofen, dimetindene, quinidine, metoprolol, release rate over 6-7 hours. propanolol, Oxprenolol, pindolol, atenolol, metoprolol, dis 0101 The release profile of the matrix tablets containing opyramide, Verapamil, diltiazem, gallopamil, nifedipine, diprophylline likewise shows uniform delayed release (FIG. nicardipine, nisoldipine, nimodipine, amlodipine, theophyl 2/2). The release of active substance was determined over 6 line, Salbutamol, terbutaline, ambroXol, aminophylline, cho hours in a paddle device at 50 rpm in 900 ml of water using line theophyllinate, pyridoStigmine, piretanide, furosemide, a Perkin-Elmer Lambda 20 UV-VIS spectrometer at 274 nm. pentoxifylline, naftidrofuryl, buflomedil, Xanthinol nicoti 1. Dispersion Suitable for use as coating agent and binder nate, bencyclane, allopurinol, norephedrine, chlorphe for pharmaceutical forms, having a solids content of 10-70% namine, isosorbide mononitrate, isosorbide dinitrate, glyc by weight consisting of erol trinitrate, molsidomine, beZafibrate, fenofibrate, gemfibrozil, cerivastatin, pravastatin, fluvastatin, lovastatin, a) from 90 to 99% by weight of a methacrylate copolymer atorvastatin, Simvastatin, Xanthinol, methoclopramide, ami consisting of at least 90% by weight of (meth)acrylate triptyline, dibenzepine, Venlafaxine, thioridazine, monomers containing neutral radicals and having a oxazepam, lithium, nitrofurantoin, dry plant extract, ascor glass transition temperature Tg of from -20°C. to +20 bic acid and potassium and the Salts thereof used pharma C. as determined by the DSC method, and ceutically. b) 1-10% by weight of a nonionic emulsifier having an 8. Pharmaceutical form comprising an active pharmaceu HLB of from 15.2 to 17.3. tical Substance, characterized in that the active Substance is 2. Dispersion according to claim 1, characterized in that bound or coated with an emulsion polymer obtained from a the methacrylate copolymer consists of from 20 to 50% by dispersion according to one or more of claims 1 to 5 by weight of methyl methacrylate, from 80 to 50% by weight drying. of ethyl acrylate and, if desired, from 0 to 10% by weight of methacrylic acid.