Title of Invention	AQUEOUS DISPERSION SUITABLE FOR THE PRODUCTION OF COATINGS AND BINDERS FOR SOLID ORAL DRUGS
Abstract	An aqueous dispersion for the production of binders or coatings for solid oral drugs having a water content of 90-40 wt. % and a solids portion of 10-60 wt. %, whereby said solids portion is composed of: (A) 10-99 wt. % of a polymer mixture consisting of: (a) 75-99 wt. % of a polymethacrylate copolymer consisting of up to 98-85 wt. % of alkyl (meth)acrylate monomers with -C4 alkyl residues and up to 2-15 wt. % of alkyl (meth)acrylate monomers with a quaternary ammolUUln group in the alkyl residue, and (b) 25-1 wt.% of ill1 alkali salt of carboxymethylcellulose having a weight average molecular weight of less than 150,000, and ..

Title of Invention

AQUEOUS DISPERSION SUITABLE FOR THE PRODUCTION OF COATINGS AND BINDERS FOR SOLID ORAL DRUGS

Abstract

An aqueous dispersion for the production of binders or coatings for solid oral drugs having a water content of 90-40 wt. % and a solids portion of 10-60 wt. %, whereby said solids portion is composed of: (A) 10-99 wt. % of a polymer mixture consisting of: (a) 75-99 wt. % of a polymethacrylate copolymer consisting of up to 98-85 wt. % of alkyl (meth)acrylate monomers with -C4 alkyl residues and up to 2-15 wt. % of alkyl (meth)acrylate monomers with a quaternary ammolUUln group in the alkyl residue, and (b) 25-1 wt.% of ill1 alkali salt of carboxymethylcellulose having a weight average molecular weight of less than 150,000, and ..

Full Text	The present invention relates to an aqueous dispersion suitable for the production of binders and coatings for solid oral drugs, containing as the solid portion, a polymer mixture A) consisting of a polymethacrylate copolymer and an alkali salt of carboxymethylcellulose and B) the customary added ingredients. The invention also relates to the applications of the dispersion. Description of the Background Water-soluble nonionic polysaccharide derivatives, for example, hydroxypropylmethylcellulose (HPMC), are routinely used for the granulation of tablet mixtures and for simple coating of solid drugs. Less often, soluble ionic polysaccharides, for example, sodium carboxymethylcellulose (Na-CMC), are used. However, both polymers form coatings that quickly dissolve in water and have a high permeability. Therefore, the protective and insulating effect in drugs is limited. The binding ability of these materials for pigments is also limited, so that the covering power of coatings for strongly colored cores is not sufficient. Furthermore, hydrophilic, strongly swelling polymers tend to form clumps when stirred in water, which must be avoided by means of special dissolution methods. DE 4,021,678 Al describes a method for the production of small formed pieces containing etofibrate, and controlled release of active ingredients by mixtm-e of the active ingredients with a physiologically neutral colloid that is insoluble in water and one that is soluble or swells in water, and subsequent extrusion. The colloids that are insoluble in water and are water-soluble or capable of swelling can be used in a ratio of 1; 10 to 90:1. Etofibrate can, for example, be mixed together with a polymethacrylic acid ester with quaternary ammonium groups (EUDRAGIT® RS) and sodium carboxymethylcellulose in the ratio 2:1. The goal is to achieve a release which is as constant as possible over a period of 4-6 h. EP 0 793 959 describes formulations with controlled release of active ingredients that are coated with a substance that is insoluble in water and a polymer capable of swelling, that has no basic groups. In the long list of substances that can potentially be used, polymethacrylate copolymers with quaternary ammonium groups (EUDRAGIT® RS) are named among the substances that are insoluble in water. Sodium carboxymethylcellulose is listed among the substances that are capable of swelling. No concrete indication of combining these two polymers is present in the disclosure of the publication. Summary of the Invention Accordingly, one object of the invention is to provide a coating and binder for solid oral drugs that, on one hand releases active ingredients for drugs quickly and without affecting the pH value, and on the other hand, which makes possible a good insulating effect in thin coatings, as well as high pigment binding ability and reliable protection of flavor. Another object of the invention is to provide an aqueous polymer dispersion for drug formulations which, as an applied coating, is not impeded by swelling and adhesion. Briefly, these objects and other objects of the invention as hereinafter will become more readily apparent can be attained by an aqueous dispersion for the production of binders or coatings for solid oral drugs having a water content of 90-40 wt.% and a solids portion of 10-60 wt.%, whereby said solids portion is composed of: (A) 10-99 wt.% of a polymer mixture consisting of: (a) 75-99 wt.% of a polymethacrylate copolymer consisting of up to 98-85 wt.% of alkyl (meth)acrylate monomers with C]-C4 alkyl residues and up to 2-15 wt.% of alkyl (meth)acrylate monomers with a quaternary ammonium group in the alkyl residue, and (b) 25-1 wt.% of an alkali salt of carboxymethylcellulose having a weight average molecular weight of less than 150,000, and (B) 90-1 wt.% of at least one substance normally added to pharmaceutical formulations. Detailed Description of the Preferred Embodiments The polymer mixture A consisting of components (a) and (b) in the stated quantity ratio is decisive for the properties of the coatings and binders for solid oral drugs which are produced from the dispersion. In the process, it is indispensable for the two components to be present in an aqueous medium, because the advantageous effects cannot be achieved when an organic solution is used (see Comparison Example 19). It is presumed that polymers (a) and (b) aggregate with one another in an advantageous manner in the aqueous phase either first in the dispersion itself or during the application of the dispersion, or during the evaporation of the water. Surprisingly, by increasing the quantity of component (b), there is an increase in tensile strength of the coated product, but a reduction of elongation at break. The binders or coatings that can be produced from the dispersion have a good mechanical strength (see Example 10), but disintegrate, as desired, very quickly in artificial gastric juice. The release of the active ingredients is practically constant and independent of the pH. In fact, disintegration of the prepared pharmaceutical coatings occurs in less than 30 min for a polymer coating of 2 mg/cm^ in artificial gastric juice. The protection of flavor is very reliable (see Example 9), and the pigment binding ability is high (see Example 8). Water content and particle size The water content of the dispersion is in the customary range of 90-40 wt.%, preferably 80-50 wt.%. The average particle size of the particulate matter in the dispersion is in the range of 50-500 nm. Polymer mixtures A Component (a) A portion of polymer mixture A consisting of components (a) and (b), to a large extent insoluble in water, is formed by a (meth)acrylate copolymer (a) that consist of up to 98-85 wt.%, preferably up to 96-88 wt.%, of alkyl (meth)acrylate monomers with C1-C4 alkyl residues, and up to 2-15 wt.%, preferably up to 4-12 wt.% of alkyl (meth)acrylate monomers having a quaternary ammonium group in the alkyl residue. Suitable alkyl (meth)acrylate monomers having C1-C4 alkyl residues include methyl acrylate, ethyl acrylate, butyl acrylate, butyl methacrylate, and methyl methacrylate. The copolymer contains 20-40 wt.%o, especially 25-35 wt% ethyl acrylate and 50-70 wt.%, especially 55-70 wt.% methyl methacrylate. Suitable alkyl (meth)acrylate monomers having quaternary ammonium groups can be found, for example, in EP 0 181 515. Disclosed examples include acryl and methacryloxytrimethylammonium chloride or the methosulfate, benzyldimethylammonium methyl methacrylate chloride, diethylmethylammonium ethyl acrylate and methacrylate methosulfate, N-trimethylammonium propyl methacrylamide chloride and N-trimethylammonium 2,2-dimethylpropyl-l-methacrylate chloride. 2-Trimethyl ammonium methyl methacrylate chloride is specially preferred. Preferably, the (meth)acrylate copolymer having quaternary ammonium groups corresponding to component (a), can be composed of 65 or 60 wt.% methyl methacrylate, 30 \vt.% ethyl acrylate and 5 or 10 wt.% 2-trimethylammonium methyl methacrylate chloride (EUDRAGIT® RS or RL) . The copolymers (a) are obtained by known techniques such as radical, solution, bead, or emulsion polymerization. They can be present as an extruded granulate, ground or spray-dried powder, or as a dispersion, for example, with 30 wt,% solid material. Component (b) The water-soluble component (b) of polymer mixture A consisting of components (a) and (b) is formed by alkali salts of carboxymethylcellulose having a molecular weight (weight average) of less than 150,000, preferably 5,000-100,000, especially preferably, 7,000-70,000. If the molecular weight of component (b) is 150,000 or more, there may be a thickening of the batch may occur, so that it can practically no longer be processed. Suitable alkali salts include lithium, sodium and potassium, as well as ammonium salts. Preferably, sodium salts are used. The viscosity of a 2% solution in water at 20 °C is usually in the range of 1-200 mPas, preferably 2-60 mPas. Preferably such types are used which, because of their method of production, contain only small portions of native fiber. Mixture ratio of components fa) and (b) The amount of component (b) employed is 1-25 wt.%, preferably 5-15%, especially preferably 5-10 wt.%, relative to the amount of polymethacrylate that is insoluble in water. The dispersions of the invention can be produced by mixing components (a) and (b) in powder form (see Example 13), or in the molten state (see Example 14), and in each case, subsequent absorption in water. The two components may also be present already as a dispersion or aqueous solution, and can be mixed directly (see Example 15). An extrusion of the powder mixture with subsequent comminution to ensure an even distribution of the two components and then absorption in water is also a practical technique. Processing into a film is done by drying, preferably during application of the spray. The energy required for evaporation of the water can be obtained by the heated process air generated, by microwaves, or by other radiation, optionally in a vacuum as well. Fundamentally, the polymers used must be nontoxic and they must present no risk to patients when used in pharmaceutical agents. B) Customary additional ingredients The dispersion of the invention contains the usual additional ingredients in quantities of 90-1 wt.% relative to polymer mixture A consisting of components (a) and (b). Quantities used and application of the customary additional ingredients in drug coatings are familiar to one of skill in the art. Customary additional ingredients include, for example, softeners, antiblocking agents, pigments, stabilizers, antioxidants, wetting agents, expanding agents, brighteners, aromatic substances or flavorings. They serve primarily as processing aids, and should ensure a safe and reproducible production method, as well as good long-term storage stability. They are added to the liquid polymer formulations before processing and can influence the permeability of the coatings, a characteristic that can be exploited, if desired, as an additional control parameter. Softeners Substances suitable as softeners generally have a molecular weight ranging from 100-2,000, and contain one or more hydrophilic groups in the molecule, for example, hydroxyl, ester, or amino groups. Suitable examples of softeners include citric acid alkyl ester, glycerin ester, phthalic acid alkyl ester, sebacic acid alkyl ester, sucrose ester, sorbitan ester, dibutyl sebacate, and polyethylene glycols 200-2,000. Preferred softeners include triethyl citrate and acetyl triethyl citrate. Esters that generally are liquid at room temperature, such as citrates, phthalates, sebacates, or castor oil, may also be mentioned. Customary quantities of softeners used in the coatings and binders of the invention range from 5-30 wt.% relative to the polymer. Antiblocking agents These substances, which generally have lipophilic properties are added to the spray suspensions and prevent an agglomeration of the cores during the fdm coating process. Preferred are talc, Mg or Ca stearate, powdered silicic acid, kaolin and nonionic emulsifiers having an HLB value ranging from 3-8. The usual quantities used for antiblocking agents in the coatings and binders of the invention range from 0-50 wt.% relative to the polymer. Pigments The addition is only rarely made in the form of a soluble dye. Generally, aluminum or iron oxide pigments are dispersed in a medium. Titanium dioxide is used as a white pigment. Quantities normally used in the coatings and binders of the invention range from 20-60 wt.% relative to the polymer mixture. Because of the high pigment binding ability, however, quantities of up to 80 wt.% can also be processed. Aside from whiteners, antiblocking agents and pigments, stabilizers, antioxidants, wetting agents, expanding agents, brighteners, aromas and flavoring agents can be named as other substances that are customarily added and known to one of skill in the art. Application as a binder Application as a binder is made by spraying the dispersion onto cores that have no active ingredients (nonpareils) with the simultaneous addition of powdered active ingredients or their mixtures. Furthermore, a dispersion that contains active ingredients can also be processed into a film so that a sheet-like pharmaceutical form is produced. Another embodiment is the spraying of the dispersion together with the active ingredients dissolved or suspended in it. /\ppiiuaumi an i^uaiui^ Core Carriers for coatings include capsules, tablets, granulates, pellets and crystals of regular or irregular shape. The size of granulates, pellets, or crystals ranges from 0.01-2.5 mm, that of tablets from 2.5-30.0 mm. Capsules consist of gelatins, starches and cellulose derivatives. They generally contain the biologically active substance (active ingredient) in an amount of up to 95%, as well as other inactive pharmaceutical ingredients up to 99.9 wt.%. Customary production methods include direct pressing, pressing of dry, wet, or sintered granulates, extrusion and subsequent rounding, wet or dry granulation and direct pelletizing (for example, on plates), or by binding of powders (powder layering) to spheres (nonpareils) or particles that contain an active ingredient. Aside from the active ingredient, they may contain other inactive pharmaceutical ingredients including binders such as cellulose and its derivatives, polyvinylpyrrolidone (PVP), humectants, disintegration accelerators, lubricants, disintigrants, (meth)acrylates, starch and its derivatives, sugar solubilizing agents and the Uke. Of particular significance is the disintegration time of the core, which influences the release of the active ingredient. Today, short disintegration times of less than 5 or less than 10 min in the disintegration test according to the European Pharmacopoeia are desirable. Longer disintegration times are problematic because additional coatings further delay the release of the active ingredient and can jeopardize the therapeutic effect. At present, a disintegration time of 30 min is regarded as the limiting value. A small effect on the pH of the disintegration medium is advantageous. Therefore, tests are done in water and artificial gastricjuice(O.lNHCl). Incorporated pharmaceutical substances can elicit an uneven coloring or unpleasant, bitter taste. In order to improve the patient acceptance of such products, taste insulation for at least 30 sec is targeted (see Examples 9 and 16 in this regard). The cores employed are homogeneous or have a layered construction. If engravings are made in the surface, they should as much as possible be only lightly covered by coatings. Coatings The layer thickness of the applied polymer mixtures of the invention varies greatly and depends on the processing method or the quantity of additional substances. The thickness ranges from l-lOO /^m, preferably from 10-50 jj^m. On customary tablets, this corresponds to a polymer application of 0.5-5 wt.%. The function of the polymer mixture in the final pharmaceutical product can be multifaceted: • protection from harmful environmental effects of moisture, gases, light, and the like. • odor or taste insulation • identification by color • mechanical stabilization • insulation from intolerable ingredients • avoidance of adhesion to the mucous membranes. The low viscosity of the polymer mixture in the aqueous dispersion, even with high portions of solid substances up to 30%, is also advantageous, because engravings on the surface of tablets can be reproduced in detail. Especially advantageous is the good protective and insulating effect of the polymer mixture of the invention with a simultaneously small effect on the disintegration of the tablets. Especially in comparison to simple coatings with HPMC, taste insulation of more than 30 sec can be achieved even with minimal polymer applications of 1 wt.%. Although thicker coatings improve disguising of the taste, they extend the disintegration time. Also advantageous is the reliable covering of dye cores by coatings with a high pigment content. A special embodiment shape is the encapsulation of a second active ingredient into the coating on a core that contains active ingredient. Application of the film coating The method of application of the dispersion is by casting, painting, or spray application from an aqueous dispersion, by suspension, by liquification, or by direct application of powder. In the process, it is critical to the embodiment that regular, closed coatings are produced. For the method of application by state of the state of the art procedures see, for example, Bauer, Lehmaim, Osterwald, Rothgang, "Coated drugs," Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, Chapter 7, pp. 165-196. For the properties relevant to the application, required tests and specifications are listed in pharmacopoeia. Details can be found in the current textbooks, for example: • R. Voigt (1984): Lehrbuch der pharmazeutischen Technologic [Textbook of pharmaceutical technology]; Verlag Chemie, Weinheim Beerfield Beach/Florida - Basel. • H. Sucker, P. Fuchs, P. Speiser: Pharmazeutische Technologic [Pharmaceutical technology], Georg Thieme Verlag Stuttgart (1991), especially Chapters 15 and 16, pp. 626-642. • A.R. Gennaro (Editor), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania (1985), Chapter 88, pp. 1567-1573. • P.H. List (1982): Arzneiformenlehre [Science of drugs], Wissenschaftliche Verlagsgesellschafl mbH, Stuttgart. Biologically Active Substances (or active pharmaceutical substances) Biologically active substances (or active pharmaceutical substances) which can be formulated with the present coating material are those which are intended to be applied to or in the human or animal body, in order to: 1. cure, alleviate, prevent, or diagnose diseases, pain, physical injuries, or ailments. 2. to aid in determining the quality, condition, or functions of the body or mental conditions. 3. to replace active ingredients or bodily fluids generated by the human or animal body. 4. to combat, eliminate or render harmless agents of disease, parasites, or substances foreign to the body or 5. to influence the quality, condition, or functions of the body or mental conditions. Conventional pharmaceutical substances can be found in reference books, such as the Red List or Merck Index. According to the invention, all active ingredients can be used that fulfill the desired therapeutic effect in the sense of the above definition, and have sufficient thermal stability. Important examples (groups and individual substances) without claiming to be comprehensive are the following: analgesics antiallergy and antiarrhythmic drugs antibiotics, chemotherapeutics, antidiabetics, antidotes, antiepileptics, antihypertensives, antihypotensives, anticoagulants, antimycotics, antiphlogistics, beta blockers, calcium antagonists, and ACE inhibitors, broncholytics/antiasthmatics, cholinergics, corticosteroids (internal) dermatics, diuretics, enzyme inhibitors, enzyme preparations and transport proteins expectorants, geriatric agents, antipodagrics, flu remedies, hormones and their inhibitors, hypnotics/sedatives, cardiac drugs, lipid reducing agents parathyroid hormones/calcium metabolism regulators, psychopharmaceuticals, sexual hormones and their inhibitors, spasmolytics, sympatholytics, sympathomimetics, vitamins, wound treatment agents, cytostatics. Preferred active ingredients for delayed release of active ingredients include: Nifedipine, diltiazem, theophylline, diclofenac sodium, ketoprofen, ibuprofen, indomethacin. ambroxol, terbutaline, vincamine, propranolol, pentoxifylline, codeine, morpliine, etilefrin, carbamazepine, and their salts that are used in therapy. Application forms Fundamentally, the described drugs can be administered directly by oral application. The granular powders, pellets, or particles produced according to the invention may be filled into gelatin capsules, bags (sachets), or suitable multidose containers with a dosing device. Intake is in solid form or as liquid suspensions. Through compression with or after the admixture of other inactive ingredients, tablets are obtained that disintegrate after intake and release the subunits that usually are coated. Also conceivable is the encapsulation of agglomerates in polyethylene glycol or lipids for the production of suppositories or vaginal drugs. Coated tablets are packed in blister or multiple-dose containers and removed by the patient directly before intake. Having now generally described the invention, a further understanding can be obtained by reference to certain specific examples which are provided herein for purpose of illustration only and are not intended to be limiting unless otherwise specified, EXAMPLES Examples 1-24 are summarized in the following tables; components (a) and (b) correspond to (a) and (b) in Claim 1. Examples 16-20 are comparative examples, which are not within the scope of the invention. Abbreviations employed in Table 1 below are as follows PMl = polymethacrylate copolymer consisting of 10 wt.% trimethylaramonium ethyl methacrylate chloride, 60 wt.% methyl methacrylate, and 30 wt.% ethyl acrylate PM2 = copolymer consisting of 5 wt.% trimethylammonium methyl methacrylate chloride, 65 wt.% methyl methacrylate, and 30 wt.% ethyl acrylate PM3 = copolymer consisting of 30 wt.% ethyl acrylate, and 70 wt.% methyl methacrylate. Na-CMC type 1 = sodium carboxymethylcellulose with a molecular weight (Mw) of approximately 50,000, degree of substitution: 0.65-0.90, alkali content (%) Na: 7.0-8.9, 2% viscosity in water at 20°C: 25-50 mPas. Na-CMC type 2 = sodium carboxymethylcellulose with a molecular weight (Mw) of approximately 20,000, degree of substitution: 0.7, alkali content (%) Na: 7.0, 2% viscosity in water at 20°C: 2-3 mPas. Na-CMC type 3 = sodium carboxymethylcellulose with a molecular weight (Mw) of approximately 65,000, degree of substitution: 0.6-0.8, alkali content (%) Na: Na-CMC type 4 = sodium carboxymethyl cellulose with a molecular weight (Mw) of approximately 250,000, degree of substitution: 0.65-0.9, alkali content (%) Na: 7.0-8.9, 2% viscosity in water at 25X: 400-600 mPas 1. rroieciive coaiing on laoieis: ypyo iNa-i^ivn^ iypc 11 9 g talc, 4 g triethy] citrate, and 0.9g Na-CMC Type 1 are mixed with 86 g water in a beaker, and evenly dispersed by means of Ultra Turrax T 50 deflocculating agent (Jahnke and Kunkel Co.). Subsequently, the suspension is slowly poured into 60 g of a 30% dispersion of PMl (Eudragit RL 30 D), which has been placed in a stainless steel container, and mixed with regular stirring. This spray suspension is applied to 1000 g of tablets as shown in column I in Table 2 above in a coating pan by means of a spray gun (spray pressure 0.8 bar) over a period of 23 min. The total application totals 2.0 mg polymer consisting of EUDRAGIT RL 30 D per cm^ tablet surface. During the application procedure, partial quantities with 1 and 1.5 mg polymer application/ CM tablet surface are removed. All coated tablets are dried for 24 h at 40'C. The coated tablets exhibit a smooth and even surface and disintegrate in the disintegration test according to the European Pharmacopoeia in purified water and artificial gastric juice within the following times (Table 4): 2. Protective coating on tablets: riO% Na-CMC Type 1 14 g talc, 6 g triethyl citrate, and 2.8 g Na-CMC Type 1 are mixed with 139 g water in a beaker, and evenly dispersed by means of Ultra Turrax T 50 deflocculating agent (Jahnlce and Kunkel Co.)- Subsequently, the suspension is slowly poured into 93 g of a 30% dispersion of polymer PMl which has been placed in a stainless steel container, and mixed with stirring. This spray suspension is applied to 1500 g of tablets according to column II in Table 2 in a coating pan by means of a spray gun (spray pressure 0.8 bar) over a period of 42 min. The application totals 2.0 mg polymer PMl per cm^ tablet surface. During the process of application, partial quantities at 1 and 1.5 mg polymer application/cm^ tablet surface are removed. All coated tablets are dried for 24 hr at 40°C. The coated tablets exhibit a smooth and even surface and disintegrate in the disintegration test according to the European Pharmacopoeia in purified water and artificial gastric juice within the times shown in following Table 5: 3. Protective coating on tablets: n5%Na-CMC Type 1) 9 g talc, 4 g triethyl citrate, and 2.7 g Na-CMC Type 1 are mixed with 94 g water in a beaker, and evenly dispersed by means of Ultra Turrax T 50 deflocculating agent (Jahnke and Kunkel Co.). Subsequently, the suspension is slowly poured into 60 g of a 30% dispersion of polymer PMl that has been put in a stainless steel container, and mixed with regular stirring. This spray suspension is applied to 1000 g of tablets according to column T in Table 2 above in a coating pan by means of a spray gun (spray pressure 0.8 bar) over a period of 33 min. The total application totals 2.0 mg polymer PMl per cm" tablet surface. During the application procedure, partial quantities with 1 and 1.5 mg polymer application/cm^ tablet surface are removed. All coated tablets are dried for 24 h at 40°C. The coated tablets exhibit a smooth and even surface and disintegrate in the disintegration test according to the European Pharmacopoeia in purified water and artificial gastric juice within the times shown in following Table 6: 4. Protective coating on tablets: r20% Na-CMC Type I) 9 g talc, 4 g triethyl citrate, and 3.6 g Na-CMC Type 1 are mixed with 98 g water in a beaker, and evenly dispersed by means of Ultra Turrax T 50 deflocculating agent (Jahnke and Kunkel Co.). Subsequently, the suspension is slowly poured into 60 g of a 30% dispersion of polymer PMl that has been put in a stainless steel container, and mixed with regular stirring. This spray suspension is apphed to 1000 g of tablets according to column I in Table 2 in a coating pan by means of a spray gun (spray pressure 0.8 bar) over a period.of 33 min. The total application totals 2.0 mg polymer PMl per cm^ tablet surface. During the application process, partial quantities with 1 and 1.5 mg polymer application/cm^ tablet surface are removed. All coated tablets are d^ied for 24 h at 40 °C. The coated tablets exhibit a smooth and even surface and disintegrate in the disintegration test according to the European Pharmacopoeia ni purified water and artificial gastric juice within the times shown in following Table 7: 5. Protective coating on tablets: (Na-CMC Type 21 9 g talc, 4 g triethyl citrate, and 2 g Na-CMC Type 2 are mixed with 90 g water in a beaker, and evenly dispersed by means of Ultra Turrax T 50 deflocculating agent (Jalinke and Kunkel Co.)- Subsequently, the suspension is slowly poured into 60 g of a 30% dispersion of polymer PMl which has been placed in a stainless steel container, and mixed with stirring. This spray suspension is applied to 1000 g of tablets according to column I in Table 2 in a coating pan by means of a spray gun (spray pressure 0.8 bar) over aperiod of 30 min. The total application totals 2.0 mg PMl per cm^ tablet surface. During the application process, partial quantities with 1 and 1.5 mg polymer application/cm^ tablet surface are removed. All coated tablets are dried for 24 h at 40°C. The coated tablets exhibit a smooth and even surface and disintegrate in the disintegration test according to the European Pharmacopoeia in purified water and artificial gastric juice within the times shown in following Table 8: 6. Protective coating on tablets: (Na-CMC Type 3) 13.8 g talc, 5.5 g triethyl citrate, and 2.8 9 Na-CMC Type 3 are mixed with 134.2 g water in a beaker, and evenly dispersed by means of Ultra Turrax T 50 deflocculating agent (Jahnke and Kunkel Co.). Subsequently, the suspension is slowly poured into 92 g of a 30% dispersion of polymer PMl which has been placed in a stainless steel container, and mixed with stirring. This spray suspension is applied to 1500 g of tablets according to column I in Table in a coating pan by means of a spray gun (spray pressure 0.8 bar) over a period of 27 min. The total application totals 2.0 mg polymer per cm^ tablet surface. During the application procedure, partial quantities with 1 and 1.5 mg polymer application/cm^ tablet surface are removed. All coated tablets are dried for 24 hr at 40°C. The coated tablets exhibit a smooth and even surface and disintegrate in the disintegration test according to the European Pharmacopoeia in purified water and artificial gastric juice within the times shown in the following Table 9: 7. Protective coating on tablets 9 g talc, 4 g triethyl citrate, and 1.8 g Na-CMC Type 1 are mixed with 90 g water in a beaker, and evenly dispersed by means of Ultra Turrax T 50 deflocculating agent (Jahnke and Kunkel Co.). Subsequently, the suspension is slowly poured in 60 g of a 30% dispersion of polymer PM2 that has been put into a stainless steel container, and mixed with regular stirring. This spray suspension is applied to 1000 g of tablets according to column T in Table 2 in a coating pan by means of a spray gun (spray pressure 0.9 bar) over a period of 26 min. The total application totals 2.0 mg polymer PM2 per cm^ tablet surface. During the application process, partial quantities with 1 and 1.5 mg polymer application/cm^ tablet surface are removed. All coated tablets are dried for 24 h at 40""C. The coated tablets exhibit a smooth and even surface and disintegrate in the disintegration test according to the European Pharmacopoeia in purified water and artificial gastric juice within the times in following Table 10: 8. Colored coating on tablets 66 g talc, 5 g triethyl citrate, and 102 g of a 33% polyethylene glycol 6000 solution in water, 118 g titanium dioxide, and 3 g quinoline gel black E 104 are mixed with 548 g water in a beaker, and evenly dispersed by means of Ultra Turrax T 50 deflocculating agent (Jahnke and Kunkel Co.). Subsequently, 83 g of a 30% dispersion of polymer PMl are put in a stainless steel container, and with stirring, 3 g of a 33% Tween 80 solution in water and 100 g of a 5% Na-CMC Type 1 solution in water are added. While stirring, the dispersed inactive ingredients are added. This spray suspension is applied to 2500 g of dark-colored tablets according to column V in Table 2 in a coating pan by means of a spray gun (spray pressure 1 bar) over a period of 81 min. The total application totals 1.4 mg polymer PMl per cm^ tablet surface. During the application procedure, partial quantities with 1 and 1.5 mg polymer application/cm^ tablet surface are removed. All coated tablets are dried for 17 h at 40°C. The tablets exhibit a smooth and even yellow surface and disintegrate in the disintegration test according to the European Pharmacopoeia in purified water after 22-35 min: 9. Taste insulation 21 g talc and 8 g triethyl citrate are mixed with 128 g water in a beaker and evenly dispersed by means of Ultra Turrax T 50 detlocculating agent (Jahnke and Kunkel Co.). Subsequently, the suspension is slowly poured into a mixture of 137 g of a 30% dispersion of polymer PMl, 6 g of a 33% Tween 80 solution in water, and 80 g of a 5% Na-CMC Type 1 solution in water which has been placed in a stainless steel container and the batch is mixed with regular stirring. This spray suspension is apphed to 1500 g of tablets according to column III in the table in a coating pan by means of a spray gun (spray pressure 0.8 bar) over a period of 72 min. The total application totals 3.0 mg polymer PMl per cm^ tablet surface. During the application procedure, partial quantities with 1.0, 1.5, 2.0, and 2.5 mg polymer application/cm^ tablet surface are removed. All coated tablets are dried for 24 h at 40°C. The tablets with a polymer application of 3 mg/cm' disintegrate in the disintegration test according to the European Pharmacopoeia in purified water and artificial gastric juice after 18-30 min. The masking of the bitter-tasting active ingredient in the tablets was determined by 4 test subjects (mean values) as shown in Table 11: 10. Stabilization of the surface (abrasion^ 21 g talc and 8 g triethyi citrate are mixed with 128 g water in a beaker and evenly dispersed by means of Ultra Turrax T 50 deflocculating agent (Jahnke and Kunkel Co.). Subsequently, the suspension is slowly poured into a mixture of 137 g of a 30% dispersion of polymer PMl, 6 g of a 33% Tween 80 solution in water, and 80 g of a 5% NA-CMC Type 1 solution in water that has been put in a stainless steel container and the batch is mixed with regular stirring. This spray suspension is applied to 1500 g of tablets according to 111 in the table in a coating pan by means of a spray gun (spray pressure 0.8 bar) over a period of 72 min. The total application totals 3.0 mg polymer per cm^ tablet surface. The coated tablets are dried for 24 h at 40°C. In the friability test according to USP 23, the tablets exhibit the values as shown in following Table 12: 11. Protective coating on particles in a fluidized bed device: 25 g talc and 10 g triethyi citrate are mixed with 61 g water in a beaker and evenly dispersed by means of an Ultra Tmrax T 50 deflocculating agent (Jahnke and Kunkel Co.). Subsequently, the suspension is slowly poured into a mixture of 167 g of a 30% dispersion of polymer PMl, 8 g of a 33% Tween 80 solution in water, and 100 g of a 5% Na-CMC Type 1 solution in water, which has been placed in a stainless steel container, and the batch is mixed with stirring. This spray suspension is applied to 1000 g potassixim chloride crystals (particle size 0.3-1 mm) in a fluidized bed device Glatt GPCG 1 by means of a spray gun (spray pressure 2 bar) over a period of 63 min. The total application amounts to 5% polymer PMl. The coated crystals are dried over 24 h at 40°C. The coated crystals mask the taste for approximately 5 sec, and in the friability test analogous to USP 23 paddle device in water, exhibit the values shown in Table 13: 12. Coating on capsules 12 g talc and 5 g triethyl citrate are mixed with 80 g water in a beaker and evenly dispersed by means of Ultra Turrax T 50 deflocculating agent (Jahnke and Kunkel Co.). Subsequently, the suspension is slowly poured into a mixture of 80 g of a 30% dispersion of polymer PMl, 3 g of a 33% Tween 80 solution in water, and 40 g of a 5% Na-CMC Type 1 solution in water, which has been placed in a stainless steel container, and the batch is mixed with stirring. This spray suspension is applied to 1000 g hard gelatin capsules according to column VI in Table 2 in a coating pan by means of a spray gun (spray pressure 0.8 bar)over a period of 47 min. The total application amounts to 3.0 mg polymer PMl per cm^ capsule surface. The coated capsules are dried over 24 hr at 40°C. The capsules with a polymer application of 3 mg/cm^ disintegrate in the disintegration test according to the European Pharmacopoeia in purified water and artificial gastric juice after 9-15 min. in the release test according to USP 23 rotating basket method in 0. IN HCl, the capsules exhibit the values shown in following Table 14: 13. Production of a spray-dried polymer mixture 12154 g of a 30% dispersion of polymer PMl are placed in a stainless steel container and stirred evenly with an electric stirrer. By means of a hose pump, a mixture of 7293 g of a 5% aqueous solution of Na-CMC Type 1 and 553 g of a 33% aqueous solution of Tween 80 are slowly metered in. The resulting mixture is dried by conventional spray-drying technology. The resulting powder is free-flowing and can be redispersed in demineralized water. 14. Production of the polymer mixture by mehing In a stainless steel container, 100 g of polymer PMl in powder form, 10 g Na-CMC Type 1, and 40 g triethyl citrate are mixed and homogeneously melted in a drying chamber at 120 °C. The mixture was comminuted after cooling by means of an IKA analytical mill. 23 g of the milled material are mixed with 207 g water and stirred for 24 h at 20° C with a magnetic stirrer. The suspension is dried in a drying chamber in a flat dish at 40°C. A homogeneous, cohesive, elastic film is produced. 15. Production of the polymer mixture by direct suspension (mixing^ of the powder 50 g polymer PMl in powder form and 5 g Na-CMC Type 1 are stirred in 450 g water by means of a magnetic stirrer. Subsequently, 10 g triethyl citrate are added and stirred for another 60 min. The suspension is dried in a drying chamber in a flat dish at 40°C. A homogeneous, cohesive, elastic film is produced. 16. (Comparative Example): Taste insulation with hydroxypropylcellulose In a beaker, 41 g of hydroxypropylcellulose (HPMC) axe dissolved in 200 g water heated to 60'C. 2 g talc and 4 g polyethylene glycol 6000 are mixed with 145 g water and evenly dispersed by means of Ultra Tinrax T 50 deflocculating agent (Jalmke and Kunkel Co.). Subsequently, the suspension is slowly poured into the HPMC solution. This spray suspension is applied to 1500 g tablets according to column III in Table 2 by means of a spray gun (spray pressure 2.5 bar) over a period of 98 min. The total application amounts to 3.0 mg HPMC per cm^ tablet surface. During the application procedure, partial quantities with 1.0, 1.5, 2.0, and 2.5 mg polymer application/ cm^ tablet surface are removed. All coated tablets are dried for 24 h at 40° C. The masking of the bitter tasting active ingredient in the tablets is determined by 4 test subjects (mean values) as shovm in Table 15: 17. (Comparative Example): Coating with xanthan 9 g talc, 4 g triethyl citrate, and 400 g of a 0.5% aqueous solution of xanthan gum are mixed with 77 g water in a beaker and evenly dispersed by means of Ultra Turrax T 50 deflocculating agent (Jahnke and Kunkel Co.). Subsequently, the suspension is slowly poured into 60 g of a 30% dispersion of PMl which has been placed in a stainless steel container, and the batch is mixed with stirring. This spray suspension is applied to 1000 g tablets according to column I in 1 able 2 in a coating pan by means of a spray gun (spray pressure 0.9 bar) over a period of 70 min. The total application amounts to 2.0 mg polymer PMl per cm^ tablet surface. During the application procedure, partial quantities of 1 and 1.5 mg polymer application/cm^ tablet surface are removed. All coated tablets are dried over 24 h at 40 °C. The coated tablets exhibit a smooth and even surface, and disintegrate in the disintegration test according to the European Pharmacopoeia in purified water and artificial gastric juice after the times shown in Table 16: 18. (Comparative RxampleV. Coating with a polvmethacrylate dispersion not according to the invention 13.8 g talc and 56 g of a,5% aqueous solution of Na-CMC Type 1 are mixed with 59 g water in a beaker and evenly dispersed by means of Ultra Turrax T 50 deflocculating agent (Jahnke and Kunkel Co.). Subsequently, the suspension is poured slowly in 92 g of a 30% aqueous dispersion of polymer PM3 which has been placed into a stainless steal container, and the batch is mixed under regular stirring. This spray suspension is applied to 1500 g of tablets according to column I in Table 2 in a coating pan by means of a spray gun (spray pressure 0.8 bar) over a period of 60 min. The total application totals 2.0 mg polymer consisting of EUDRAGTT NE 30 D per cm^ tablet surface. During the application procedure, partial quantities with 1 and 1.5 mg polymer application/cm^ tablet surface are removed. All coated tablets are dried for 24 h at 40 °C. The coated tablets exhibit a smooth and even surface and disintegrate in the disintegration test according to the European Pharmacopoeia in purified water and artificial gastric juice within the times shown in Table 17: / 19. (Comparative Example): Coating of organic solution: In a bealcer, 11 g granular powder of polymer PMl, 5.5 g talc, 2.2 g triethyl citrate, and 1.1 g Na-CMC Type 1 dissolved in 11.3 g water are mixed with 215.7 g ethanol, and dispersed by means of Ultra Turrax T 50 deflocculating agent (Jahnke and Kunkel Co.) This spray suspension is apphed to 600 g of tablets according to column I in Table 18 in a coating pan by means of a spray gun (spray pressure 0.6 bar) over a period of 26 min. The total application totals 2,0 mg polymer PMl per cm^ tablet surface. During the application procedure, partial quantities with 1 and 1.5 mg poiymer application/cm^ tablet surface are removed. All coated tablets are dried for 2 hr at 40°C. The coated tablets exhibit a smooth and even surface and disintegrate in the disintegration test according to the European Pharmacopoeia in purified water and artificial gastric juice within the times shown in following Table 18: 20. ^Comparative Example^ N A-CMC with too high a molecular weight: Protective coating on tablets: 9 g talc, 4 g triethyl citrate, and 2 g Na-CMC Type 4-with a molecular weight of approximately 250,000, and 90 g water are mixed in a beaker, and evenly dispersed by means of Ultra Turrax T 50 deflocculating agent (Jahnke and Kunkel Co.). Subsequently, the suspension is slowly poured in 60 g of a 30% aqueous dispersion of polymer PMl which has been placed into a stainless steel container, and the batch is mixed under stirring. A viscous, semifluid mass is formed that cannot be processed by conventional spray application. 21. Chewable tablets consisting of coated crystals 346 g of coated potassium chloride crystals according to Example 11 are mixed with 75 g Avicel PH, 102.75 g corn starch, 2.5 g Aerosil 200, and 1.5 g magnesium stearate in an eccentric tumbler, and then pressed into tablets using an eccentric press (Korsch EK 0 Typee) with the following galenic data: diameter 10 mm, weight 375 mg, breaking strength 20-30N, disintegration in demineralized water and O.IN HCl 23. Coating on tablets consisting of redispersed powder In a beaker, 100 g of spray-dried product from Example 13 are dispersed in 233 g water by means of Ultra Turrax T 50 within 10 min. In a beaker, 13.8 g talc and 5.5 g triethyl citrate are mixed with 130 g water and evenly dispersed by means of Ultra Turrax T 50 deflocculating agent (Jahnke and Kunkel Co.). Subsequently, the suspension is slowly poured into 106.1 g of the redispersion produced previously, which has been placed in a stainless steel container, and the batch is mixed with stirring. This spray suspension is applied to 1500 g of tablets according to column I in Table 2 in a coating pan by means of a spray gun (spray pressure 0.8 bar) over a period of 60 min. The total application totals 2,0 mg polymer PMl per cm^ tablet surface. During the application procedure, partial quantities with 1 and 1.5 mg polymer application/cm^ tablet surface are removed. All coated tablets are dried for 24 hr at 40°C. The coated tablets exhibit a smooth and even surface and disintegrate in the disintegration test according to the European Pharmacopoeia in purified water and artificial gastric juice within the times shown in following Table 21: 24. Production of the polymer mixture with spray-dried polymer PM2 50 g powder from a spray-dried 30% aqueous dispersion of polymer PM2 are redispersed in 200 g water by means of a magnetic stirrer for 60 min, and subsequently 5 g Na-CMC Type 1 as well as 200 g water are stirred by means of a magnetic stirrer and mixed for another 2 h. Subsequently, 10 g triethyl citrate are added and stirred for another 15 min. The suspension is dried in a flat dish at 40° C in a drying chamber. A homogeneous, cohesive, elastic film is formed. The disclosure of German Priority application Serial No. 198 09 719.0 filed March 6, 1998 is hereby incorporated by reference into the present application. Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings. It is, therefore, to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein. WE CLAIM: 1. An aqueous dispersion for the production of binders or coatings for solid oral drugs having a water content of 90-40 wt.% and a solids portion of 10-60 wt.%, whereby said solids portion is composed of: (A) 10-99 wt.% of a polymer mixture consisting of: (a) 75-99 wt.% of a polymethacryJate copolymer consisting of up to 98-85 wt,% of alkyl (meth)acrylate monomers with C1-C4 alkyl residues and up to 2-15 wt.% of alkyl (meth)acrylate monomers with a quaternary ammonium group in the alkyl residue, and (b) 25-1 wt.% of an alkali salt of carboxymethylcellulose having a weight average molecular weight of less than 150,000, and (B) 90-t wt% of at least one substance normally added to pharmaceutical formulations. 2. The aqueous dispersion according to Claim 1, wherein said C1-4 alkyl (meth)acryiate monomer is methyl acrylate, ethyl acrylate, butyl acrylate, butyl methacrylate or methyl methacrylate. 3. The aqueous dispersion according to Claim 1, wherein said alkyl (meth)acrylate monomer with a quaternary ammonium group in the alkyl residue is acryl or methacryloxytrimethylammonium chloride or the methosulfate, benzyldimethylammonium methyl methacrylate chloride, diethylmethylammonium ethyl acrylate or methacrylate meihosulfate, N-trimethylammonium propyl metbacrylamide chloride, N-trimethylammonium 2,2-dimethylpropyl-l-methacryiate chloride or 2-trimethyIammonium methyl methacrylate chloride. 4. The aqueous dispersion according to Claim 1, wherein said carboxymethylcellulose has a weight average molecular weight ranging from 5,000 to 100,000. 5. The aqueous dispersion according to Claim 1, wherein said at least one substance (B) is a softener, antiblocking agent, pigment, stabilizer, antioxidant, wetting agent, expanding agent, brightener, aromatic substance or flavoring agent. 6. A redispersable powdered prepared by spray drying the dispersion as claimed in claim 1. 7. A method of preparing a shaped drug preparation, comprising: coating the surface of a shaped drug material with the aqueous dispersion of Claim 1, thereby providing a drug with a quickly disintegrating coating. 8. The method according to Claim 7, wherein the disintegration time of the drug coating is less than 30 min for an applied polymer coating of 2 mg/cm^ in artificial gastric juice. 9. The method according to Claim 7, wherein the shaped drug materia! is in the shape of a capsule, a tablet, a granulate, a pellet or a regularly or irregularly shaped crystal of a size ranging from 0.01 to 2.5 mm. 10. The method according to claim 9, wherein the tablet is of a size ranging from 2.5 to 30 mm. I i. The method according to claim 9, wherein the dispersion is applied by spraying. 12. A method of preparing a drug formulation, comprising: employing the dispersion of claim 1 as a binder for an active pharmaceutical ingredient. 13. A method of preparing shaped drug preparation, comprising: spraying the surface of a shaped core in a known manner with a the dispersion of claim 1 which contains no active ingredient while simultaneously adding active powdered active ingredient or their mixtures to the core. 14. A pharmaceutical product prepared by the methods as claimed in claims 6 to 12.

Full Text

The present invention relates to an aqueous dispersion suitable for the production of binders and coatings for solid oral drugs, containing as the solid portion, a polymer mixture A) consisting of a polymethacrylate copolymer and an alkali salt of carboxymethylcellulose and B) the customary added ingredients. The invention also relates to the applications of the dispersion.
Description of the Background
Water-soluble nonionic polysaccharide derivatives, for example, hydroxypropylmethylcellulose (HPMC), are routinely used for the granulation of tablet mixtures and for simple coating of solid drugs. Less often, soluble ionic polysaccharides, for example, sodium carboxymethylcellulose (Na-CMC), are used. However, both polymers form coatings that quickly dissolve in water and have a high permeability. Therefore, the protective and insulating effect in drugs is limited. The binding ability of these materials for pigments is also limited, so that the covering power of coatings for strongly colored cores is not sufficient. Furthermore, hydrophilic, strongly swelling polymers tend to form clumps when stirred in water, which must be avoided by means of special dissolution methods.

DE 4,021,678 Al describes a method for the production of small formed pieces containing etofibrate, and controlled release of active ingredients by mixtm-e of the active ingredients with a physiologically neutral colloid that is insoluble in water and one that is soluble or swells in water, and subsequent extrusion. The colloids that are insoluble in water and are water-soluble or capable of swelling can be used in a ratio of 1; 10 to 90:1. Etofibrate can, for example, be mixed together with a polymethacrylic acid ester with quaternary ammonium groups (EUDRAGIT® RS) and sodium carboxymethylcellulose in the ratio 2:1. The goal is to achieve a release which is as constant as possible over a period of 4-6 h.
EP 0 793 959 describes formulations with controlled release of active ingredients that are coated with a substance that is insoluble in water and a polymer capable of swelling, that has no basic groups. In the long list of substances that can potentially be used, polymethacrylate copolymers with quaternary ammonium groups (EUDRAGIT® RS) are named among the substances that are insoluble in water. Sodium carboxymethylcellulose is listed among the substances that are capable of swelling. No concrete indication of combining these two polymers is present in the disclosure of the publication.
Summary of the Invention
Accordingly, one object of the invention is to provide a coating and binder for solid oral drugs that, on one hand releases active ingredients for drugs quickly and without affecting the pH value, and on the other hand, which makes possible a good insulating effect in thin coatings, as well as high pigment binding ability and reliable protection of flavor.
Another object of the invention is to provide an aqueous polymer dispersion for drug formulations which, as an applied coating, is not impeded by swelling and adhesion.

Briefly, these objects and other objects of the invention as hereinafter will become more readily apparent can be attained by an aqueous dispersion for the production of binders or coatings for solid oral drugs having a water content of 90-40 wt.% and a solids portion of 10-60 wt.%, whereby said solids portion is composed of:
(A) 10-99 wt.% of a polymer mixture consisting of:
(a) 75-99 wt.% of a polymethacrylate copolymer consisting of up to 98-85 wt.% of alkyl (meth)acrylate monomers with C]-C4 alkyl residues and up to 2-15 wt.% of alkyl (meth)acrylate monomers with a quaternary ammonium group in the alkyl residue, and (b) 25-1 wt.% of an alkali salt of carboxymethylcellulose having a weight average molecular weight of less than 150,000, and
(B) 90-1 wt.% of at least one substance normally added to pharmaceutical
formulations.
Detailed Description of the Preferred Embodiments
The polymer mixture A consisting of components (a) and (b) in the stated quantity ratio is decisive for the properties of the coatings and binders for solid oral drugs which are produced from the dispersion. In the process, it is indispensable for the two components to be present in an aqueous medium, because the advantageous effects cannot be achieved when an organic solution is used (see Comparison Example 19). It is presumed that polymers (a) and (b) aggregate with one another in an advantageous manner in the aqueous phase either first in the dispersion itself or during the application of the dispersion, or during the evaporation of the water. Surprisingly, by increasing the quantity of component (b), there is an increase in

tensile strength of the coated product, but a reduction of elongation at break. The binders or coatings that can be produced from the dispersion have a good mechanical strength (see Example 10), but disintegrate, as desired, very quickly in artificial gastric juice. The release of the active ingredients is practically constant and independent of the pH. In fact, disintegration of the prepared pharmaceutical coatings occurs in less than 30 min for a polymer coating of 2 mg/cm^ in artificial gastric juice. The protection of flavor is very reliable (see Example 9), and the pigment binding ability is high (see Example 8).
Water content and particle size
The water content of the dispersion is in the customary range of 90-40 wt.%, preferably 80-50 wt.%. The average particle size of the particulate matter in the dispersion is in the range of 50-500 nm.
Polymer mixtures A
Component (a)
A portion of polymer mixture A consisting of components (a) and (b), to a large extent insoluble in water, is formed by a (meth)acrylate copolymer (a) that consist of up to 98-85 wt.%, preferably up to 96-88 wt.%, of alkyl (meth)acrylate monomers with C1-C4 alkyl residues, and up to 2-15 wt.%, preferably up to 4-12 wt.% of alkyl (meth)acrylate monomers having a quaternary ammonium group in the alkyl residue.
Suitable alkyl (meth)acrylate monomers having C1-C4 alkyl residues include methyl acrylate, ethyl acrylate, butyl acrylate, butyl methacrylate, and methyl methacrylate. The copolymer contains 20-40 wt.%o, especially 25-35 wt% ethyl acrylate and 50-70 wt.%,

especially 55-70 wt.% methyl methacrylate.
Suitable alkyl (meth)acrylate monomers having quaternary ammonium groups can be found, for example, in EP 0 181 515. Disclosed examples include acryl and methacryloxytrimethylammonium chloride or the methosulfate, benzyldimethylammonium methyl methacrylate chloride, diethylmethylammonium ethyl acrylate and methacrylate methosulfate, N-trimethylammonium propyl methacrylamide chloride and N-trimethylammonium 2,2-dimethylpropyl-l-methacrylate chloride. 2-Trimethyl ammonium methyl methacrylate chloride is specially preferred.
Preferably, the (meth)acrylate copolymer having quaternary ammonium groups corresponding to component (a), can be composed of 65 or 60 wt.% methyl methacrylate, 30 \vt.% ethyl acrylate and 5 or 10 wt.% 2-trimethylammonium methyl methacrylate chloride (EUDRAGIT® RS or RL) .
The copolymers (a) are obtained by known techniques such as radical, solution, bead, or emulsion polymerization. They can be present as an extruded granulate, ground or spray-dried powder, or as a dispersion, for example, with 30 wt,% solid material.
Component (b)
The water-soluble component (b) of polymer mixture A consisting of components (a) and (b) is formed by alkali salts of carboxymethylcellulose having a molecular weight (weight average) of less than 150,000, preferably 5,000-100,000, especially preferably, 7,000-70,000. If the molecular weight of component (b) is 150,000 or more, there may be a thickening of the batch may occur, so that it can practically no longer be processed. Suitable alkali salts include lithium, sodium and potassium, as well as ammonium salts. Preferably,

sodium salts are used. The viscosity of a 2% solution in water at 20 °C is usually in the range of 1-200 mPas, preferably 2-60 mPas. Preferably such types are used which, because of their method of production, contain only small portions of native fiber.
Mixture ratio of components fa) and (b)
The amount of component (b) employed is 1-25 wt.%, preferably 5-15%, especially preferably 5-10 wt.%, relative to the amount of polymethacrylate that is insoluble in water.
The dispersions of the invention can be produced by mixing components (a) and (b) in powder form (see Example 13), or in the molten state (see Example 14), and in each case, subsequent absorption in water. The two components may also be present already as a dispersion or aqueous solution, and can be mixed directly (see Example 15). An extrusion of the powder mixture with subsequent comminution to ensure an even distribution of the two components and then absorption in water is also a practical technique.
Processing into a film is done by drying, preferably during application of the spray. The energy required for evaporation of the water can be obtained by the heated process air generated, by microwaves, or by other radiation, optionally in a vacuum as well.
Fundamentally, the polymers used must be nontoxic and they must present no risk to patients when used in pharmaceutical agents.
B) Customary additional ingredients
The dispersion of the invention contains the usual additional ingredients in quantities of 90-1 wt.% relative to polymer mixture A consisting of components (a) and (b). Quantities used and application of the customary additional ingredients in drug coatings are familiar to

one of skill in the art. Customary additional ingredients include, for example, softeners, antiblocking agents, pigments, stabilizers, antioxidants, wetting agents, expanding agents, brighteners, aromatic substances or flavorings. They serve primarily as processing aids, and should ensure a safe and reproducible production method, as well as good long-term storage stability. They are added to the liquid polymer formulations before processing and can influence the permeability of the coatings, a characteristic that can be exploited, if desired, as an additional control parameter.
Softeners
Substances suitable as softeners generally have a molecular weight ranging from 100-2,000, and contain one or more hydrophilic groups in the molecule, for example, hydroxyl, ester, or amino groups. Suitable examples of softeners include citric acid alkyl ester, glycerin ester, phthalic acid alkyl ester, sebacic acid alkyl ester, sucrose ester, sorbitan ester, dibutyl sebacate, and polyethylene glycols 200-2,000. Preferred softeners include triethyl citrate and acetyl triethyl citrate. Esters that generally are liquid at room temperature, such as citrates, phthalates, sebacates, or castor oil, may also be mentioned.
Customary quantities of softeners used in the coatings and binders of the invention range from 5-30 wt.% relative to the polymer.
Antiblocking agents
These substances, which generally have lipophilic properties are added to the spray suspensions and prevent an agglomeration of the cores during the fdm coating process. Preferred are talc, Mg or Ca stearate, powdered silicic acid, kaolin and nonionic emulsifiers

having an HLB value ranging from 3-8. The usual quantities used for antiblocking agents in the coatings and binders of the invention range from 0-50 wt.% relative to the polymer.
Pigments
The addition is only rarely made in the form of a soluble dye. Generally, aluminum or iron oxide pigments are dispersed in a medium. Titanium dioxide is used as a white pigment. Quantities normally used in the coatings and binders of the invention range from 20-60 wt.% relative to the polymer mixture. Because of the high pigment binding ability, however, quantities of up to 80 wt.% can also be processed.
Aside from whiteners, antiblocking agents and pigments, stabilizers, antioxidants, wetting agents, expanding agents, brighteners, aromas and flavoring agents can be named as other substances that are customarily added and known to one of skill in the art.
Application as a binder
Application as a binder is made by spraying the dispersion onto cores that have no active ingredients (nonpareils) with the simultaneous addition of powdered active ingredients or their mixtures. Furthermore, a dispersion that contains active ingredients can also be processed into a film so that a sheet-like pharmaceutical form is produced.
Another embodiment is the spraying of the dispersion together with the active ingredients dissolved or suspended in it.

/\ppiiuaumi an i^uaiui^
Core
Carriers for coatings include capsules, tablets, granulates, pellets and crystals of regular or irregular shape. The size of granulates, pellets, or crystals ranges from 0.01-2.5 mm, that of tablets from 2.5-30.0 mm. Capsules consist of gelatins, starches and cellulose derivatives.
They generally contain the biologically active substance (active ingredient) in an amount of up to 95%, as well as other inactive pharmaceutical ingredients up to 99.9 wt.%.
Customary production methods include direct pressing, pressing of dry, wet, or sintered granulates, extrusion and subsequent rounding, wet or dry granulation and direct pelletizing (for example, on plates), or by binding of powders (powder layering) to spheres (nonpareils) or particles that contain an active ingredient.
Aside from the active ingredient, they may contain other inactive pharmaceutical ingredients including binders such as cellulose and its derivatives, polyvinylpyrrolidone (PVP), humectants, disintegration accelerators, lubricants, disintigrants, (meth)acrylates, starch and its derivatives, sugar solubilizing agents and the Uke.
Of particular significance is the disintegration time of the core, which influences the release of the active ingredient. Today, short disintegration times of less than 5 or less than 10 min in the disintegration test according to the European Pharmacopoeia are desirable. Longer disintegration times are problematic because additional coatings further delay the release of the active ingredient and can jeopardize the therapeutic effect. At present, a disintegration time of 30 min is regarded as the limiting value. A small effect on the pH of the disintegration medium is advantageous. Therefore, tests are done in water and artificial

gastricjuice(O.lNHCl).
Incorporated pharmaceutical substances can elicit an uneven coloring or unpleasant, bitter taste. In order to improve the patient acceptance of such products, taste insulation for at least 30 sec is targeted (see Examples 9 and 16 in this regard).
The cores employed are homogeneous or have a layered construction. If engravings are made in the surface, they should as much as possible be only lightly covered by coatings.
Coatings
The layer thickness of the applied polymer mixtures of the invention varies greatly and depends on the processing method or the quantity of additional substances. The thickness ranges from l-lOO /^m, preferably from 10-50 jj^m. On customary tablets, this corresponds to a polymer application of 0.5-5 wt.%.
The function of the polymer mixture in the final pharmaceutical product can be multifaceted:
• protection from harmful environmental effects of moisture, gases, light, and the like.
• odor or taste insulation
• identification by color
• mechanical stabilization
• insulation from intolerable ingredients
• avoidance of adhesion to the mucous membranes.
The low viscosity of the polymer mixture in the aqueous dispersion, even with high portions of solid substances up to 30%, is also advantageous, because engravings on the

surface of tablets can be reproduced in detail.
Especially advantageous is the good protective and insulating effect of the polymer mixture of the invention with a simultaneously small effect on the disintegration of the tablets. Especially in comparison to simple coatings with HPMC, taste insulation of more than 30 sec can be achieved even with minimal polymer applications of 1 wt.%. Although thicker coatings improve disguising of the taste, they extend the disintegration time.
Also advantageous is the reliable covering of dye cores by coatings with a high pigment content. A special embodiment shape is the encapsulation of a second active ingredient into the coating on a core that contains active ingredient.
Application of the film coating
The method of application of the dispersion is by casting, painting, or spray application from an aqueous dispersion, by suspension, by liquification, or by direct application of powder. In the process, it is critical to the embodiment that regular, closed coatings are produced.
For the method of application by state of the state of the art procedures see, for example, Bauer, Lehmaim, Osterwald, Rothgang, "Coated drugs," Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, Chapter 7, pp. 165-196.
For the properties relevant to the application, required tests and specifications are listed in pharmacopoeia.
Details can be found in the current textbooks, for example:
• R. Voigt (1984): Lehrbuch der pharmazeutischen Technologic [Textbook of
pharmaceutical technology]; Verlag Chemie, Weinheim Beerfield

Beach/Florida - Basel.
• H. Sucker, P. Fuchs, P. Speiser: Pharmazeutische Technologic [Pharmaceutical technology], Georg Thieme Verlag Stuttgart (1991), especially Chapters 15 and 16, pp. 626-642.
• A.R. Gennaro (Editor), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania (1985), Chapter 88, pp. 1567-1573.
• P.H. List (1982): Arzneiformenlehre [Science of drugs], Wissenschaftliche Verlagsgesellschafl mbH, Stuttgart.
Biologically Active Substances (or active pharmaceutical substances)
Biologically active substances (or active pharmaceutical substances) which can be formulated with the present coating material are those which are intended to be applied to or in the human or animal body, in order to:
1. cure, alleviate, prevent, or diagnose diseases, pain, physical injuries, or ailments.
2. to aid in determining the quality, condition, or functions of the body or mental conditions.
3. to replace active ingredients or bodily fluids generated by the human or animal body.
4. to combat, eliminate or render harmless agents of disease, parasites, or substances foreign to the body or
5. to influence the quality, condition, or functions of the body or mental conditions.

Conventional pharmaceutical substances can be found in reference books, such as the
Red List or Merck Index.
According to the invention, all active ingredients can be used that fulfill the desired
therapeutic effect in the sense of the above definition, and have sufficient thermal stability. Important examples (groups and individual substances) without claiming to be
comprehensive are the following: analgesics
antiallergy and antiarrhythmic drugs antibiotics, chemotherapeutics, antidiabetics, antidotes, antiepileptics, antihypertensives, antihypotensives, anticoagulants, antimycotics, antiphlogistics, beta blockers, calcium antagonists, and ACE inhibitors, broncholytics/antiasthmatics, cholinergics, corticosteroids (internal) dermatics, diuretics, enzyme inhibitors, enzyme preparations and transport proteins
expectorants, geriatric agents, antipodagrics, flu remedies, hormones and their inhibitors, hypnotics/sedatives, cardiac drugs, lipid reducing agents
parathyroid hormones/calcium metabolism regulators, psychopharmaceuticals, sexual hormones and their inhibitors, spasmolytics, sympatholytics, sympathomimetics, vitamins, wound treatment agents, cytostatics. Preferred active ingredients for delayed release of active ingredients include:
Nifedipine, diltiazem, theophylline, diclofenac sodium, ketoprofen, ibuprofen, indomethacin.

ambroxol, terbutaline, vincamine, propranolol, pentoxifylline, codeine, morpliine, etilefrin, carbamazepine, and their salts that are used in therapy.
Application forms
Fundamentally, the described drugs can be administered directly by oral application. The granular powders, pellets, or particles produced according to the invention may be filled into gelatin capsules, bags (sachets), or suitable multidose containers with a dosing device. Intake is in solid form or as liquid suspensions.
Through compression with or after the admixture of other inactive ingredients, tablets are obtained that disintegrate after intake and release the subunits that usually are coated. Also conceivable is the encapsulation of agglomerates in polyethylene glycol or lipids for the production of suppositories or vaginal drugs.
Coated tablets are packed in blister or multiple-dose containers and removed by the patient directly before intake.
Having now generally described the invention, a further understanding can be obtained by reference to certain specific examples which are provided herein for purpose of illustration only and are not intended to be limiting unless otherwise specified,
EXAMPLES Examples 1-24 are summarized in the following tables; components (a) and (b) correspond to (a) and (b) in Claim 1. Examples 16-20 are comparative examples, which are not within the scope of the invention.

Abbreviations employed in Table 1 below are as follows
PMl = polymethacrylate copolymer consisting of 10 wt.%
trimethylaramonium ethyl methacrylate chloride, 60 wt.% methyl
methacrylate, and 30 wt.% ethyl acrylate
PM2 = copolymer consisting of 5 wt.% trimethylammonium methyl
methacrylate chloride, 65 wt.% methyl methacrylate, and 30 wt.% ethyl
acrylate
PM3 = copolymer consisting of 30 wt.% ethyl acrylate, and 70 wt.% methyl
methacrylate.
Na-CMC
type 1 = sodium carboxymethylcellulose with a molecular weight (Mw) of
approximately 50,000, degree of substitution: 0.65-0.90, alkali content
(%) Na: 7.0-8.9, 2% viscosity in water at 20°C: 25-50 mPas.
Na-CMC
type 2 = sodium carboxymethylcellulose with a molecular weight (Mw) of
approximately 20,000, degree of substitution: 0.7, alkali content (%)
Na: 7.0, 2% viscosity in water at 20°C: 2-3 mPas.
Na-CMC
type 3 = sodium carboxymethylcellulose with a molecular weight (Mw) of
approximately 65,000, degree of substitution: 0.6-0.8, alkali content
(%) Na: Na-CMC
type 4 = sodium carboxymethyl cellulose with a molecular weight (Mw) of
approximately 250,000, degree of substitution: 0.65-0.9, alkali content

(%) Na: 7.0-8.9, 2% viscosity in water at 25X: 400-600 mPas

1. rroieciive coaiing on laoieis: ypyo iNa-i^ivn^ iypc 11
9 g talc, 4 g triethy] citrate, and 0.9g Na-CMC Type 1 are mixed with 86 g water in a beaker, and evenly dispersed by means of Ultra Turrax T 50 deflocculating agent (Jahnke and Kunkel Co.). Subsequently, the suspension is slowly poured into 60 g of a 30% dispersion of PMl (Eudragit RL 30 D), which has been placed in a stainless steel container, and mixed with regular stirring. This spray suspension is applied to 1000 g of tablets as shown in column I in Table 2 above in a coating pan by means of a spray gun (spray pressure 0.8 bar) over a period of 23 min. The total application totals 2.0 mg polymer consisting of EUDRAGIT RL 30 D per cm^ tablet surface. During the application procedure, partial quantities with 1 and 1.5 mg polymer application/ CM tablet surface are removed. All coated tablets are dried for 24 h at 40'C.
The coated tablets exhibit a smooth and even surface and disintegrate in the disintegration test according to the European Pharmacopoeia in purified water and artificial gastric juice within the following times (Table 4):

2. Protective coating on tablets: riO% Na-CMC Type 1
14 g talc, 6 g triethyl citrate, and 2.8 g Na-CMC Type 1 are mixed with 139 g water in a beaker, and evenly dispersed by means of Ultra Turrax T 50 deflocculating agent (Jahnlce

and Kunkel Co.)- Subsequently, the suspension is slowly poured into 93 g of a 30% dispersion of polymer PMl which has been placed in a stainless steel container, and mixed with stirring. This spray suspension is applied to 1500 g of tablets according to column II in Table 2 in a coating pan by means of a spray gun (spray pressure 0.8 bar) over a period of 42 min. The application totals 2.0 mg polymer PMl per cm^ tablet surface. During the process of application, partial quantities at 1 and 1.5 mg polymer application/cm^ tablet surface are removed. All coated tablets are dried for 24 hr at 40°C. The coated tablets exhibit a smooth and even surface and disintegrate in the disintegration test according to the European Pharmacopoeia in purified water and artificial gastric juice within the times shown in following Table 5:

3. Protective coating on tablets: n5%Na-CMC Type 1)
9 g talc, 4 g triethyl citrate, and 2.7 g Na-CMC Type 1 are mixed with 94 g water in a beaker, and evenly dispersed by means of Ultra Turrax T 50 deflocculating agent (Jahnke and Kunkel Co.). Subsequently, the suspension is slowly poured into 60 g of a 30% dispersion of polymer PMl that has been put in a stainless steel container, and mixed with regular stirring. This spray suspension is applied to 1000 g of tablets according to column T in Table 2 above

in a coating pan by means of a spray gun (spray pressure 0.8 bar) over a period of 33 min. The total application totals 2.0 mg polymer PMl per cm" tablet surface. During the application procedure, partial quantities with 1 and 1.5 mg polymer application/cm^ tablet surface are removed. All coated tablets are dried for 24 h at 40°C.
The coated tablets exhibit a smooth and even surface and disintegrate in the disintegration test according to the European Pharmacopoeia in purified water and artificial gastric juice within the times shown in following Table 6:

4. Protective coating on tablets: r20% Na-CMC Type I)
9 g talc, 4 g triethyl citrate, and 3.6 g Na-CMC Type 1 are mixed with 98 g water in a beaker, and evenly dispersed by means of Ultra Turrax T 50 deflocculating agent (Jahnke and Kunkel Co.). Subsequently, the suspension is slowly poured into 60 g of a 30% dispersion of polymer PMl that has been put in a stainless steel container, and mixed with regular stirring. This spray suspension is apphed to 1000 g of tablets according to column I in Table 2 in a coating pan by means of a spray gun (spray pressure 0.8 bar) over a period.of 33 min. The total application totals 2.0 mg polymer PMl per cm^ tablet surface. During the application process, partial quantities with 1 and 1.5 mg polymer application/cm^ tablet surface are

removed. All coated tablets are d^ied for 24 h at 40 °C.
The coated tablets exhibit a smooth and even surface and disintegrate in the disintegration test according to the European Pharmacopoeia ni purified water and artificial gastric juice within the times shown in following Table 7:

5. Protective coating on tablets: (Na-CMC Type 21
9 g talc, 4 g triethyl citrate, and 2 g Na-CMC Type 2 are mixed with 90 g water in a beaker, and evenly dispersed by means of Ultra Turrax T 50 deflocculating agent (Jalinke and Kunkel Co.)- Subsequently, the suspension is slowly poured into 60 g of a 30% dispersion of polymer PMl which has been placed in a stainless steel container, and mixed with stirring. This spray suspension is applied to 1000 g of tablets according to column I in Table 2 in a coating pan by means of a spray gun (spray pressure 0.8 bar) over aperiod of 30 min. The total application totals 2.0 mg PMl per cm^ tablet surface. During the application process, partial quantities with 1 and 1.5 mg polymer application/cm^ tablet surface are removed. All coated tablets are dried for 24 h at 40°C.
The coated tablets exhibit a smooth and even surface and disintegrate in the disintegration test according to the European Pharmacopoeia in purified water and artificial

gastric juice within the times shown in following Table 8:

6. Protective coating on tablets: (Na-CMC Type 3)
13.8 g talc, 5.5 g triethyl citrate, and 2.8 9 Na-CMC Type 3 are mixed with 134.2 g water in a beaker, and evenly dispersed by means of Ultra Turrax T 50 deflocculating agent (Jahnke and Kunkel Co.). Subsequently, the suspension is slowly poured into 92 g of a 30% dispersion of polymer PMl which has been placed in a stainless steel container, and mixed with stirring. This spray suspension is applied to 1500 g of tablets according to column I in Table in a coating pan by means of a spray gun (spray pressure 0.8 bar) over a period of 27 min. The total application totals 2.0 mg polymer per cm^ tablet surface. During the application procedure, partial quantities with 1 and 1.5 mg polymer application/cm^ tablet surface are removed. All coated tablets are dried for 24 hr at 40°C.
The coated tablets exhibit a smooth and even surface and disintegrate in the disintegration test according to the European Pharmacopoeia in purified water and artificial gastric juice within the times shown in the following Table 9:

7. Protective coating on tablets
9 g talc, 4 g triethyl citrate, and 1.8 g Na-CMC Type 1 are mixed with 90 g water in a beaker, and evenly dispersed by means of Ultra Turrax T 50 deflocculating agent (Jahnke and Kunkel Co.). Subsequently, the suspension is slowly poured in 60 g of a 30% dispersion of polymer PM2 that has been put into a stainless steel container, and mixed with regular stirring. This spray suspension is applied to 1000 g of tablets according to column T in Table 2 in a coating pan by means of a spray gun (spray pressure 0.9 bar) over a period of 26 min. The total application totals 2.0 mg polymer PM2 per cm^ tablet surface. During the application process, partial quantities with 1 and 1.5 mg polymer application/cm^ tablet surface are removed. All coated tablets are dried for 24 h at 40""C.
The coated tablets exhibit a smooth and even surface and disintegrate in the disintegration test according to the European Pharmacopoeia in purified water and artificial gastric juice within the times in following Table 10:

8. Colored coating on tablets
66 g talc, 5 g triethyl citrate, and 102 g of a 33% polyethylene glycol 6000 solution in water, 118 g titanium dioxide, and 3 g quinoline gel black E 104 are mixed with 548 g water in a beaker, and evenly dispersed by means of Ultra Turrax T 50 deflocculating agent (Jahnke and Kunkel Co.). Subsequently, 83 g of a 30% dispersion of polymer PMl are put in a stainless steel container, and with stirring, 3 g of a 33% Tween 80 solution in water and 100 g of a 5% Na-CMC Type 1 solution in water are added. While stirring, the dispersed inactive ingredients are added.
This spray suspension is applied to 2500 g of dark-colored tablets according to column V in Table 2 in a coating pan by means of a spray gun (spray pressure 1 bar) over a period of 81 min. The total application totals 1.4 mg polymer PMl per cm^ tablet surface. During the application procedure, partial quantities with 1 and 1.5 mg polymer application/cm^ tablet surface are removed. All coated tablets are dried for 17 h at 40°C.
The tablets exhibit a smooth and even yellow surface and disintegrate in the disintegration test according to the European Pharmacopoeia in purified water after 22-35 min:

9. Taste insulation
21 g talc and 8 g triethyl citrate are mixed with 128 g water in a beaker and evenly dispersed by means of Ultra Turrax T 50 detlocculating agent (Jahnke and Kunkel Co.). Subsequently, the suspension is slowly poured into a mixture of 137 g of a 30% dispersion of polymer PMl, 6 g of a 33% Tween 80 solution in water, and 80 g of a 5% Na-CMC Type 1 solution in water which has been placed in a stainless steel container and the batch is mixed with regular stirring. This spray suspension is apphed to 1500 g of tablets according to column III in the table in a coating pan by means of a spray gun (spray pressure 0.8 bar) over a period of 72 min. The total application totals 3.0 mg polymer PMl per cm^ tablet surface. During the application procedure, partial quantities with 1.0, 1.5, 2.0, and 2.5 mg polymer application/cm^ tablet surface are removed. All coated tablets are dried for 24 h at 40°C. The tablets with a polymer application of 3 mg/cm' disintegrate in the disintegration test according to the European Pharmacopoeia in purified water and artificial gastric juice after 18-30 min.
The masking of the bitter-tasting active ingredient in the tablets was determined by 4 test subjects (mean values) as shown in Table 11:

10. Stabilization of the surface (abrasion^
21 g talc and 8 g triethyi citrate are mixed with 128 g water in a beaker and evenly dispersed by means of Ultra Turrax T 50 deflocculating agent (Jahnke and Kunkel Co.). Subsequently, the suspension is slowly poured into a mixture of 137 g of a 30% dispersion of polymer PMl, 6 g of a 33% Tween 80 solution in water, and 80 g of a 5% NA-CMC Type 1 solution in water that has been put in a stainless steel container and the batch is mixed with regular stirring. This spray suspension is applied to 1500 g of tablets according to 111 in the table in a coating pan by means of a spray gun (spray pressure 0.8 bar) over a period of 72 min. The total application totals 3.0 mg polymer per cm^ tablet surface. The coated tablets are dried for 24 h at 40°C. In the friability test according to USP 23, the tablets exhibit the values as shown in following Table 12:

11. Protective coating on particles in a fluidized bed device:
25 g talc and 10 g triethyi citrate are mixed with 61 g water in a beaker and evenly dispersed by means of an Ultra Tmrax T 50 deflocculating agent (Jahnke and Kunkel Co.). Subsequently, the suspension is slowly poured into a mixture of 167 g of a 30% dispersion of polymer PMl, 8 g of a 33% Tween 80 solution in water, and 100 g of a 5% Na-CMC Type 1 solution in water, which has been placed in a stainless steel container, and the batch is mixed

with stirring.
This spray suspension is applied to 1000 g potassixim chloride crystals (particle size 0.3-1 mm) in a fluidized bed device Glatt GPCG 1 by means of a spray gun (spray pressure 2 bar) over a period of 63 min. The total application amounts to 5% polymer PMl. The coated crystals are dried over 24 h at 40°C. The coated crystals mask the taste for approximately 5 sec, and in the friability test analogous to USP 23 paddle device in water, exhibit the values shown in Table 13:

12. Coating on capsules
12 g talc and 5 g triethyl citrate are mixed with 80 g water in a beaker and evenly dispersed by means of Ultra Turrax T 50 deflocculating agent (Jahnke and Kunkel Co.). Subsequently, the suspension is slowly poured into a mixture of 80 g of a 30% dispersion of polymer PMl, 3 g of a 33% Tween 80 solution in water, and 40 g of a 5% Na-CMC Type 1 solution in water, which has been placed in a stainless steel container, and the batch is mixed with stirring.
This spray suspension is applied to 1000 g hard gelatin capsules according to column VI in Table 2 in a coating pan by means of a spray gun (spray pressure 0.8 bar)over a period of 47 min. The total application amounts to 3.0 mg polymer PMl per cm^ capsule surface.

The coated capsules are dried over 24 hr at 40°C. The capsules with a polymer application of 3 mg/cm^ disintegrate in the disintegration test according to the European Pharmacopoeia in purified water and artificial gastric juice after 9-15 min.
in the release test according to USP 23 rotating basket method in 0. IN HCl, the capsules exhibit the values shown in following Table 14:

13. Production of a spray-dried polymer mixture
12154 g of a 30% dispersion of polymer PMl are placed in a stainless steel container and stirred evenly with an electric stirrer. By means of a hose pump, a mixture of 7293 g of a 5% aqueous solution of Na-CMC Type 1 and 553 g of a 33% aqueous solution of Tween 80 are slowly metered in. The resulting mixture is dried by conventional spray-drying technology. The resulting powder is free-flowing and can be redispersed in demineralized water.
14. Production of the polymer mixture by mehing
In a stainless steel container, 100 g of polymer PMl in powder form, 10 g Na-CMC

Type 1, and 40 g triethyl citrate are mixed and homogeneously melted in a drying chamber at 120 °C. The mixture was comminuted after cooling by means of an IKA analytical mill. 23 g of the milled material are mixed with 207 g water and stirred for 24 h at 20° C with a magnetic stirrer. The suspension is dried in a drying chamber in a flat dish at 40°C. A homogeneous, cohesive, elastic film is produced.
15. Production of the polymer mixture by direct suspension (mixing^ of the powder
50 g polymer PMl in powder form and 5 g Na-CMC Type 1 are stirred in 450 g water by means of a magnetic stirrer. Subsequently, 10 g triethyl citrate are added and stirred for another 60 min. The suspension is dried in a drying chamber in a flat dish at 40°C. A homogeneous, cohesive, elastic film is produced.
16. (Comparative Example): Taste insulation with hydroxypropylcellulose
In a beaker, 41 g of hydroxypropylcellulose (HPMC) axe dissolved in 200 g water heated to 60'C. 2 g talc and 4 g polyethylene glycol 6000 are mixed with 145 g water and evenly dispersed by means of Ultra Tinrax T 50 deflocculating agent (Jalmke and Kunkel Co.). Subsequently, the suspension is slowly poured into the HPMC solution. This spray suspension is applied to 1500 g tablets according to column III in Table 2 by means of a spray gun (spray pressure 2.5 bar) over a period of 98 min. The total application amounts to 3.0 mg HPMC per cm^ tablet surface. During the application procedure, partial quantities with 1.0, 1.5, 2.0, and 2.5 mg polymer application/ cm^ tablet surface are removed. All coated tablets are dried for 24 h at 40° C. The masking of the bitter tasting active ingredient in the tablets is determined by 4 test subjects (mean values) as shovm in Table 15:

17. (Comparative Example): Coating with xanthan
9 g talc, 4 g triethyl citrate, and 400 g of a 0.5% aqueous solution of xanthan gum are mixed with 77 g water in a beaker and evenly dispersed by means of Ultra Turrax T 50 deflocculating agent (Jahnke and Kunkel Co.). Subsequently, the suspension is slowly poured into 60 g of a 30% dispersion of PMl which has been placed in a stainless steel container, and the batch is mixed with stirring.
This spray suspension is applied to 1000 g tablets according to column I in 1 able 2 in a coating pan by means of a spray gun (spray pressure 0.9 bar) over a period of 70 min. The total application amounts to 2.0 mg polymer PMl per cm^ tablet surface. During the application procedure, partial quantities of 1 and 1.5 mg polymer application/cm^ tablet surface are removed. All coated tablets are dried over 24 h at 40 °C.
The coated tablets exhibit a smooth and even surface, and disintegrate in the disintegration test according to the European Pharmacopoeia in purified water and artificial gastric juice after the times shown in Table 16:

18. (Comparative RxampleV. Coating with a polvmethacrylate dispersion not according to the invention
13.8 g talc and 56 g of a,5% aqueous solution of Na-CMC Type 1 are mixed with 59 g water in a beaker and evenly dispersed by means of Ultra Turrax T 50 deflocculating agent (Jahnke and Kunkel Co.). Subsequently, the suspension is poured slowly in 92 g of a 30% aqueous dispersion of polymer PM3 which has been placed into a stainless steal container, and the batch is mixed under regular stirring.
This spray suspension is applied to 1500 g of tablets according to column I in Table 2 in a coating pan by means of a spray gun (spray pressure 0.8 bar) over a period of 60 min. The total application totals 2.0 mg polymer consisting of EUDRAGTT NE 30 D per cm^ tablet surface. During the application procedure, partial quantities with 1 and 1.5 mg polymer application/cm^ tablet surface are removed. All coated tablets are dried for 24 h at 40 °C.
The coated tablets exhibit a smooth and even surface and disintegrate in the disintegration test according to the European Pharmacopoeia in purified water and artificial gastric juice within the times shown in Table 17:

/
19. (Comparative Example): Coating of organic solution:
In a bealcer, 11 g granular powder of polymer PMl, 5.5 g talc, 2.2 g triethyl citrate, and 1.1 g Na-CMC Type 1 dissolved in 11.3 g water are mixed with 215.7 g ethanol, and dispersed by means of Ultra Turrax T 50 deflocculating agent (Jahnke and Kunkel Co.)
This spray suspension is apphed to 600 g of tablets according to column I in Table 18 in a coating pan by means of a spray gun (spray pressure 0.6 bar) over a period of 26 min. The total application totals 2,0 mg polymer PMl per cm^ tablet surface.
During the application procedure, partial quantities with 1 and 1.5 mg poiymer application/cm^ tablet surface are removed. All coated tablets are dried for 2 hr at 40°C. The coated tablets exhibit a smooth and even surface and disintegrate in the disintegration test according to the European Pharmacopoeia in purified water and artificial gastric juice within the times shown in following Table 18:

20. ^Comparative Example^ N A-CMC with too high a molecular weight:
Protective coating on tablets: 9 g talc, 4 g triethyl citrate, and 2 g Na-CMC Type 4-with a molecular weight of approximately 250,000, and 90 g water are mixed in a beaker, and evenly dispersed by means of Ultra Turrax T 50 deflocculating agent (Jahnke and Kunkel Co.). Subsequently, the suspension is slowly poured in 60 g of a 30% aqueous dispersion of polymer PMl which has been placed into a stainless steel container, and the batch is mixed under stirring. A viscous, semifluid mass is formed that cannot be processed by conventional spray application.
21. Chewable tablets consisting of coated crystals
346 g of coated potassium chloride crystals according to Example 11 are mixed with 75 g Avicel PH, 102.75 g corn starch, 2.5 g Aerosil 200, and 1.5 g magnesium stearate in an eccentric tumbler, and then pressed into tablets using an eccentric press (Korsch EK 0 Typee) with the following galenic data: diameter 10 mm, weight 375 mg, breaking strength 20-30N, disintegration in demineralized water and O.IN HCl

23. Coating on tablets consisting of redispersed powder
In a beaker, 100 g of spray-dried product from Example 13 are dispersed in 233 g water by means of Ultra Turrax T 50 within 10 min. In a beaker, 13.8 g talc and 5.5 g triethyl citrate are mixed with 130 g water and evenly dispersed by means of Ultra Turrax T 50 deflocculating agent (Jahnke and Kunkel Co.). Subsequently, the suspension is slowly poured into 106.1 g of the redispersion produced previously, which has been placed in a stainless steel container, and the batch is mixed with stirring.
This spray suspension is applied to 1500 g of tablets according to column I in Table 2 in a coating pan by means of a spray gun (spray pressure 0.8 bar) over a period of 60 min. The total application totals 2,0 mg polymer PMl per cm^ tablet surface. During the application procedure, partial quantities with 1 and 1.5 mg polymer application/cm^ tablet surface are removed. All coated tablets are dried for 24 hr at 40°C.
The coated tablets exhibit a smooth and even surface and disintegrate in the disintegration test according to the European Pharmacopoeia in purified water and artificial gastric juice within the times shown in following Table 21:

24. Production of the polymer mixture with spray-dried polymer PM2
50 g powder from a spray-dried 30% aqueous dispersion of polymer PM2 are
redispersed in 200 g water by means of a magnetic stirrer for 60 min, and subsequently 5 g
Na-CMC Type 1 as well as 200 g water are stirred by means of a magnetic stirrer and mixed
for another 2 h. Subsequently, 10 g triethyl citrate are added and stirred for another 15 min.
The suspension is dried in a flat dish at 40° C in a drying chamber. A homogeneous,
cohesive, elastic film is formed.
The disclosure of German Priority application Serial No. 198 09 719.0 filed March 6,
1998 is hereby incorporated by reference into the present application.
Obviously, numerous modifications and variations of the present invention are
possible in light of the above teachings. It is, therefore, to be understood that within the scope
of the appended claims, the invention may be practiced otherwise than as specifically
described herein.

WE CLAIM:
1. An aqueous dispersion for the production of binders or coatings for solid oral drugs
having a water content of 90-40 wt.% and a solids portion of 10-60 wt.%, whereby said solids
portion is composed of:
(A) 10-99 wt.% of a polymer mixture consisting of:
(a) 75-99 wt.% of a polymethacryJate copolymer consisting of up to 98-85 wt,% of alkyl (meth)acrylate monomers with C1-C4 alkyl residues and up to 2-15 wt.% of alkyl (meth)acrylate monomers with a quaternary ammonium group in the alkyl residue, and (b) 25-1 wt.% of an alkali salt of carboxymethylcellulose having a weight average molecular weight of less than 150,000, and
(B) 90-t wt% of at least one substance normally added to pharmaceutical
formulations.
2. The aqueous dispersion according to Claim 1, wherein said C1-4 alkyl (meth)acryiate monomer is methyl acrylate, ethyl acrylate, butyl acrylate, butyl methacrylate or methyl methacrylate.
3. The aqueous dispersion according to Claim 1, wherein said alkyl (meth)acrylate monomer with a quaternary ammonium group in the alkyl residue is acryl or methacryloxytrimethylammonium chloride or the methosulfate, benzyldimethylammonium methyl methacrylate chloride, diethylmethylammonium ethyl acrylate or methacrylate meihosulfate, N-trimethylammonium propyl metbacrylamide chloride, N-trimethylammonium 2,2-dimethylpropyl-l-methacryiate chloride or 2-trimethyIammonium methyl methacrylate chloride.

4. The aqueous dispersion according to Claim 1, wherein said carboxymethylcellulose has a
weight average molecular weight ranging from 5,000 to 100,000.
5. The aqueous dispersion according to Claim 1, wherein said at least one substance (B) is a
softener, antiblocking agent, pigment, stabilizer, antioxidant, wetting agent, expanding agent,
brightener, aromatic substance or flavoring agent.
6. A redispersable powdered prepared by spray drying the dispersion as claimed in claim 1.
7. A method of preparing a shaped drug preparation, comprising:
coating the surface of a shaped drug material with the aqueous dispersion of Claim 1, thereby providing a drug with a quickly disintegrating coating.
8. The method according to Claim 7, wherein the disintegration time of the drug coating is
less than 30 min for an applied polymer coating of 2 mg/cm^ in artificial gastric juice.
9. The method according to Claim 7, wherein the shaped drug materia! is in the shape of a
capsule, a tablet, a granulate, a pellet or a regularly or irregularly shaped crystal of a size
ranging from 0.01 to 2.5 mm.
10. The method according to claim 9, wherein the tablet is of a size ranging from 2.5 to 30
mm.
I i. The method according to claim 9, wherein the dispersion is applied by spraying.
12. A method of preparing a drug formulation, comprising:
employing the dispersion of claim 1 as a binder for an active pharmaceutical ingredient.
13. A method of preparing shaped drug preparation, comprising:
spraying the surface of a shaped core in a known manner with a the dispersion of claim 1 which contains no active ingredient while simultaneously adding active powdered active ingredient or their mixtures to the core.
14. A pharmaceutical product prepared by the methods as claimed in claims 6 to 12.

Documents:

238-mas-1999 abstract duplicate.pdf

238-mas-1999 abstract.pdf

238-mas-1999 claims duplicate.pdf

238-mas-1999 claims.pdf

238-mas-1999 correspondence others.pdf

238-mas-1999 correspondence po.pdf

238-mas-1999 description (complete) duplicate.pdf

238-mas-1999 description (complete).pdf

238-mas-1999 form-1.pdf

238-mas-1999 form-19.pdf

238-mas-1999 form-26.pdf

238-mas-1999 form-4.pdf

238-mas-1999 form-6.pdf

238-mas-1999 others.pdf

238-mas-1999 petition.pdf

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Patent Number

223533

Indian Patent Application Number

238/MAS/1999

PG Journal Number

47/2008

Publication Date

21-Nov-2008

Grant Date

12-Sep-2008

Date of Filing

25-Feb-1999

Name of Patentee

ROHM GMBH & CO. KG

Applicant Address

KIRSCHENALLEE 5, D-64293 DARMSTADT,

Inventors:

#	Inventor's Name	Inventor's Address
1	HANS-ULRICH PETEREIT	DEUTSCHER STAATSANGEHORIGER, HANDELSTRASSE 40, D-64291 DARMSTADT,
2	SILKE GOLZ	DEUTSCHE STAATSANGEHORIGE, HEINRICHSTRASSE 18, D-64625 BENSHEIM,
3	WOLFGANG WEISBROD	DEUTSCHE STAATSANGEHORIGER, POTSDAMER STRASSE 5, D-64331 WEITERSTADT,

PCT International Classification Number

A61K31/485

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	198 09 719.0	1998-03-06	Germany