Medicated Products Containing a Magnesium Trisilicate Adsorbent with a Medicament Drug Adsorbed Thereon

Europaisches Patentamt J number: 0132 472 European Patent Office Publication B1 Office europeen des brevets

EUROPEAN PATENT SPECIFICATION

mtci.4: A 61 K 47/00, A 61 K 31/485, Date of publication of patent specification: 21.06.89 A 61 K 31/44, A 61 K 31/135, Application number: 83306756.4 A 61 K9/00, A 61 K9/14, A 61 K 9/20, A 61 K 9/68 Date of filing: 07.11.83

medicament drug adsorbed Medicated products containing a magnesium trisilicate adsorbent with a thereon.

COMPANY Priority: 20.07.83 US 516002 Proprietor: WARNER-LAMBERT 201 Tabor Road Morris Plains New Jersey 07950 (US) Date of publication of application: 13.02.85 Bulletin 85/07 Inventor: Peters, David 8 Youngman Drive 07853 (US) Publication of the grant of the patent: Long Valley New Jersey 21.06.89 Bulletin 89/25 Inventor: Talwar, Anil K. 75 East Mill Road Long Valley New Jersey 07853 (US) Jr. Designated Contracting States: Inventor: Derrick, John, AT BE CH DE FR GB IT LI LU NL SE RD 7, Box 372 Newton New Jersey 07860 (US)

References cited: (§) et al DE-A-2217 ) Representative: Jones, Michael Raymond 652 28 DE-B-2 631 947 HASELTINE LAKE & CO. Hazlitt House GB-A-1 236 880 Southampton Buildings Chancery Lane GB-A-2 033 225 London WC2A1 AT (GB) US-A-3 085 942 US-A-3 272 594 US-A-3 449 266 CM US-A-4401674

CM CO may Note: Within nine months from the publication of the mention of the grant of the European patent any person Notice of shall give notice to the European Patent Office of opposition to the European patent granted. opposition reasoned statement. It shall not be deemed to have been filed until the opposit.on fee has been Q. be filed in a written paid. (Art. 99(1 ) European patent convention). UJ Courier Press, Leamington Spa, England. EP 0 132 472 B1

Description

This invention relates to a medicated product containing a magnesium trisilicate adsorbent and a medicament drug adsorbate adsorbed thereon and to a process for its preparation. 5 The use of magnesium trisilicates in the preparation of medicated products has been taught in the literature as a method to render bitter drug principles tasteless in liquid, tablet and chewable dosage forms and which become readily bioavailable when the medicated product reaches the low pH acid media of the stomach. U.S. Patent No. (US — A — ) 3,085,942 discloses the formation of an antitussive composition using 10 dextromethorphan and its acid addition salts adsorbed, in part, on magnesium trisilicate. This patent also discloses that particle size of the magnesium trisilicate is not critical in preparing the medicated product and that magnesium trisilicates with average particle sizes of about 0.1 to about 150 urn (microns) are usable. It is also noted that when the ingredients are intimately mixed, the bitter taste associated with dextromethorphan is reduced or eliminated. The medicated product may be mixed with other ingredients 15 to form, for example, compressed tablets, candy lozenges and chewing gum tablets. Most of these products when placed in the mouth and chewed, however, cause release of the medicament drug adsorbate from the medicated product resulting in the sensation of off-taste medicine to the user. Efforts therefore have been diverted to the development of products that either reduce the amount of medicament drug or mask the after-taste, such as by minimizing stimulation of the taste buds. 20 These methods have involved various techniques such as microencapsulation as a method of coating particles or liquid droplets with edible polymeric materials; adsorption onto substrates capable of keeping the drugs adsorbed while in the mouth but releasing them eventually in the stomach or gastrointestinal tract; spray congealing and spray coating involving taste masking of materials with fatty acids or monoglycerides and diglycerides of edible fatty acids; and formation of different salts or derivatives by 25 modification of the chemical composition of the drug substance itself. It would, therefore, be desirable to develop a medicated product that would enable such products to be made without the bitter after-taste characteristics that result from incorporating effective amounts of bitter medicament drugs, and that can be made and used easily without elaborate processing procedures. The present applicants have unexpectedly discovered that certain magnesium trisilicates, rather than so conventional magnesium trisilicates broadly, have adsorbency potentials greater than commercially available grades of magnesium trisilicates and achieve optimum medicament drug taste-masking characteristics while providing rapid bioavailability. In particular, the present applicants have found that a medicated product exhibiting unexpected results is only achieved with a magnesium trisilicate having a critical surface area, per gram, of at least 400 m2 35 when the particles of the magnesium trisilicate exhibit a flake-like structure having multiple interstitial spaces. This particular magnesium trisilicate has been found to be sutiable for preparation of tasteless medicated products. While the present invention is not to be limited to theoretical considerations, it is believed that the 40 surface area of the magnesium trisilicate coupled with the flaked-like surface results in an unusual ability to adsorp the medicament drug within the channels, convolutions or other interstitial spaces of the adsorbent. Once adsorbed within the magnesium trisilicate, the drug is not available for organoleptic taste prior to passage into the digestive tract and subsequent desorption by the gastric juice. This pronounced adsorption is not found in normal commercially available magnesium trisilicate and appears to be 45 unrelated to particle size. According to one aspect of the present invention, there is provided a medicated product comprising: a magnesium trisilicate adsorbent and a medicament drug adsorbate chosen from antitussives, antihistamines, decongestants, alkaloid materials and mixtures thereof, the amount of drug adsorbate being in the range of from 1% to 20% by weight of the medicated product; so characterised in that the magnesium trisilicate adsorbent has a flake-like structure with multiple interstitial spaces and has, per gram, a surface area of at least 400 m2, preferably at least 440 m2, more preferably from 440 to 600 m2. In this aspect of the present invention, the medicament drug is selected from: antitussive materials, preferably dextromethorphan, dextromethorphan hydrobromide, noscapine, 55 carbetapentane, citrate, chlophedianol hydrochloride and mixtures thereof, more preferably dextromethorphan or dextromethorphan hydrobromide; antihistamine materials, preferably chlorpheniramine maleate, phenindamine tartrate, pyrilamine maleate, doxylamine succinate, phenyltoloxamine citrate and mixtures thereof; decongestant materials, preferably phenylephrine hydrochloride, phenylpropanolamine so- hydrochloride, pseudoephedrine, ephedrine and mixtures thereof; and alkaloid materials, preferably codeine phosphate, codeine sulphate, morphine and mixtures thereof; and mixtures thereof. Preferably the amount of medicament drug adsorbed onto the magnesium trisilicate is in the range 65 from 5% to 15% by weight of the medicated product. EP 0 132 472 B1

According to another aspect of the present invention there is provided a process for preparing a medicated product comprising a medicament drug, chosen from antitussives, antihistamines, decongestants, alkaloid materials and mixtures thereof, adsorbed onto a magnesium trisilicate, which process comprises: 5 dissolving a medicament drug in a solvent; admixing, with the dissolved drug, a magnesium trisilicate having a flake-like structure with multiple interstitial spaces, and which has per gram, a surface area of at least 400 m2 to prepare a mass having a homogeneous consistency which enables migration of the medicament drug within the interstitial spaces of the magnesium trisilicate; and m recovering the medicated product. The medicated product of this invention may further include a pharmaceutically acceptable carrier and be in the form of a lozenge, tablet, toffee, nougat, chewy candy, and chewing gum. into For a better understanding of the present invention, and to show how the same may be carried effect, reference will be made, by way of example, to the accompanying drawings in which: 15 Figure 1 represents a photomicrograph of a magnesium trisilicate employed in the medicated product of the present invention, magnified 5000x; Figure 2 represents a photomicrograph of a medicated product containing dextromethorphan HBr adsorbate, in accordance with the present invention, magnified 5000x; Figure 3 represents a photomicrograph of a normal magnesium trisilicate magnified 5000x; and 20 Figure 4 represents a photomicrograph of a medicated product containing dextromethorphan HBr adsorbate adsorbed into normal magnesium trisilicate, magnified 5000x. The magnesium trisilicate employed in the present invention is a fine, white odourless powder free from grittiness having a surface area of at least 400 m2/g, and preferably at 440 m2/g and most preferably from 440 to 600 m2/g which has a flake-like structure with multiple interstitial spaces. It has been 25 unexpectedly found that magnesium trisilicates having these characteristics are useful as adsorbent aids in masking the bitter after-taste associated with various drug compounds. The magnesium trisilicate employed in the present invention is distinct from normally available magnesium trisilicates. The term magnesium trisilicate does not have a precise description but approximates to the formula 2MgO.3SiO2 • xH20. The physical texture and absorptive properties of 30 magnesium silicates have been heretofore varied depending predominantly upon their mode of preparation. These materials, however, generally possess a water content of 17 to 34%, a minimum of 20% magnesium oxide, a minimum of 45% silicon dioxide, and a ratio of MgO to SiO2 of 2.10 to 2.30. The normal magnesium trisilicate has a. surface area of less than 400 m2/g and preferably less than 250m2/g. These materials likewise are giobular semi-spherical structures which are non-flake in heretofore 35 appearance and are void of interstitial spaces. Such materials when used as an adsorbent have failed to effectively mask the bitter taste associated with adsorbed medication while maintaining satisfactory levels of drug activity. It is believed that such conventional materials have heretofore only been able to partially adsorb the medicament as described in U.S. Patent No. — A— 3,085,942 on the surface of the magnesium trisilicate. Since the surface of these materials is relatively smooth, efficient adsorption has 40 not been possible and additional after-taste masking ingredients have been employed. The method of making the magnesium trisilicates used in this invention is not critical and is not considered a part of this invention. Magnesium trisilicates used in the present invention are believed to occur naturally or may be prepared by standard techniques. Such techniques generally use normal reactants, such as sodium silicate and magnesium sulphate which are reacted under heat, the magnesium 45 trisilicate is precipitated and recovered. See for example U.S. Patent — A— 3,272,594. The medicament drugs used herein are chosen from antitussives, antihistamines, decongestants, alkaloid materials and mixtures thereof and their acid addition salts. Both organic and inorganic salts may be used provided the drug maintains its medicament value and is soluble in the solvent. Exemplary acid salts include hydrochloride, hydrobromide, orthophosphate, benzoate, maleate, tartrate, succinate, citrate, 50 salicylate, sulphate, and acetate. The weight percent of the drug or its acid addition salt thereof, based on the weight of the medicated product, is preferably from 1% to 20%, and most preferably 5% to 15%, which amounts will vary depending upon the therapeutic dosage permitted. The groups of drugs that are employed in the medicated product of the present invention and specific 55 examples are given below: a) Antitussives, such as dextromethorphan, dextromethorphan hydrobromide, noscapme, carbetapentane citrate, and chlophedianol hydrochloride; b) Antihistamines, such as chloropheniramine maleate, phenindamine tartrate, pyrilamine maleate, doxylamine succinate, and phenyltoloxamine citrate; 60 c) Decongestants, such as phenylephrine hydrochloride, phenylpropanolamine hydrochloride, pseudoephedrine, hydrochloride ephedrine; and d) Various alkaloids, such as codeine phosphate, codeine sulphate and morphine. These materials may be used alone or in combination on the adsorbent material within the ranges specified above. HBr. 65 A particularly effective medicated product has been prepared using dextromethorphan EP 0132 472 B1

The medicated product of the present invention can be prepared by conventional granulation and/or slurry techniques. Both processes involve the initial step of dissolving the medicament drug adsorbed in a suitable inert solvent and then mixing with the magnesium trisilicate adsorbent. Solvent concentrations may vary widely but are generally from 15% to 60% by weight of the total composition. When mixing is 5 performed with low amounts of solvent, for example 15% to 35% by weight of the total composition, the resulting granulated product is removed and dried to a predetermined moisture content between 5% and 20% by weight of the final composition. When higher solvent concentrations are employed a slurry is formed containing the drug and magnesium trisilicate. Solvent concentrations may range from 30% to 60% by weight of the total composition for optimum results. io The solvent is then removed and the medicated product recovered and used as a paste or dried to a free flowing powder. Any solvent may be used in the inventive process. To prepare the medicated product providing it is capable of dissolving the medicament drug. Representative solvents include water; polyhalogenated lower hydrocarbons such as chloroform, methylene chloride; lower alcohols, such as methanol, ethanol, 15 propanol and butanol; and aromatic solvents such as benzene, with water being the preferred solvent. The medicated product once prepared may be stored for future use or formulated with conventional additives, that is pharmaceutical ly acceptable carriers, to prepare medicated compositions which offer a variety of textures to suit particular applications. Such compositions may be in the form of a lozenge, tablet, toffee, nougat, chewy candy and chewing gum. The pharmaceutically acceptable carriers may be selected 20 from a wide range of materials. Without being limited thereto, such materials include diluents, binders and adhesives, lubricants, disintegrants, colourants, flavourings, sweeteners and miscellaneous materials such as buffers and adsorbents in order to prepare a particular medicated composition. The preparation of confectionery and chewing gum products is historically well known and has changed very little over the years. 25 Lozenges are flavoured medicated dosage forms intended to be sucked and held in the mouth. They may be in the form of various shapes, the most common being flat, circular, octagonal and biconvex forms. The lozenge bases are generally in two forms, hard, boiled candy lozenges and compressed tablet lozenges. The hard boiled candy lozenges are prepared from a mixture of sugar and other carbohydrates that are 30 kept in an amorphous or glassy condition. This form can be considered a solid syrup of sugars generally having from 0.5 to 1.5% moisture. Such materials normally contain up to 92% corn syrup, up to 55% sugar and from 0.1% to 5.0% water. The syrup component generally is prepared from corn syrups high in fructose, but may include other materials. Further ingredients such as flavourings, sweeteners, acidulents, colourants, and so forth may also be added. In contrast, compressed tablet lozenges contain particular 35 materials and are formed into structures under pressure. They generally contain sugars in amounts up to 95% and typical tablet excipients such as binders and lubricants as well as flavours or colourants. The lozenges may be made of soft confectionary materials such as those contained in nougat. These materials contain two primary components, namely a high boiling syrup such as corn syrup, and a relatively light textured frappe, generally prepared from gelatin, egg albumen, milk proteins such as casein, 40 and vegetable proteins such as soy protein, and the like. The frappe is generally relatively light, and may, for example, range in density from 0.5 to 0.7 g/ml. By comparison, the high boiling syrup, or "bob syrup", is relatively viscous and possesses a higher density, and frequently contains a substantial amount of sugar. Conventionally, the final nougat composition is prepared by the addition of the "bob syrup" to the frappe under agitation, to form the basic 45 nougat mixture. Further ingredients such as flavourings, oils or additional sugar may be added thereafter also under agitation. A general discussion of the composition and preparation of nougat confections may be found in B. W. Minifie, Chocolate, Cocoa and Confectionery: Science and Technology, 2nd edition, AVI Publishing Co., Inc., Westport, Connecticut, (1980), at Pages 424 — 425. Pharmaceutical tablets of this invention may also be in the form of chewable forms. This form is so particularly advantageous because of convenience and patient acceptance and rapid onset of bioactivity. To achieve acceptable stability and quality as well as good taste and mouth feel several considerations are important, namely amount of active substance per tablet, flavour compressibility and organoleptic properties of the drug. The preparation of chewable medicated candy is prepared by procedures similar to those used to make 55 soft confectionary. This procedure generally involves the formation of a boiled sugar-corn syrup blend to which is added a frappe mixture. The boiled sugar-corn syrup blend may be prepared from sugar and corn syrup blended in parts by weight ratio of 90 to 10:10 to 90. This blend is heated to temperatures above 120°C to remove water and to form a molten mass. The frappe is generally prepared from gelatin, egg albumen, milk proteins such as casein, and vegetable proteins such as soy protein, which are added to a 60 gelatin solution and rapidly mixed at ambient temperature to form an aerated sponge-like mass. The frappe is then added to the molten candy base and mixed until homogeneous at temperatures between 65°C and 120°C. The medicated product can then be added as the temperature of the mix is lowered to around 65°C to 93°C whereupon additional ingredients are added such as flavours and colourants. The formulation is further cooled and formed to pieces of desired dimensions. 65 A general discussion of the lozenge and chewable tablet forms of confectionery may be found in H. A. EP 0 132 472 B1

Lieberman and L Lachman, Pharmaceutical Dosage Forms: Tablets Volume 1, Marcel Dekker, Inc., New York, N.Y. at pages 289 to 466. With regard to the chewing gum formulation in particular, the amount of gum base employed will vary greatly depending on various factors such as the type of base used, consistency desired and other 5 components used to make the final product. In general, amounts of 5% to 45% by weight of the final chewing gum composition are acceptable for use in chewing gum compositions with preferred amounts of 15% to 25% by weight. The gum base may be any water-insoluble gum base well known in the art. Illustrative examples of suitable polymers in gum bases include both natural and synthetic elastomers and rubbers. For example, those polymers which are suitable in gum bases, include, without limitation, m substances of vegetable origins such as chicle, jelutong, gutta percha and crown gum. Synthetic elastomers such as butadiene-styrene copolymers, isobutylene-isoprene copolymers, polyethylene, polyisobutylene and polyvinylacetate and mixtures thereof, are particularly useful. The gum base composition may contain elastomer solvents to aid in softening the rubber component. Such elastomer solvents may comprise methyl, glycerol or pentaerythritol esters of rosins or modified 75 rosins, such as hydrogenated, dimerized or polymerized rosins or mixtures thereof. Examples of elastomer solvents suitable for use herein include the pentaerythritol ester of partially hydrogenated wood rosin, pentaerythritol ester of wood rosin, glycerol ester of wood rosin, glycerol ester of partially dimerized rosin, glycerol ester of polymerized rosin, giycerol ester of tall oil rosin, glycerol ester of wood rosin and partially hydrogenated wood rosin and partially hydrogenated methyl ester of rosin, such as polymers of a-pinene 20 or p-pinene; terpene resins including polyterpene and mixtures thereof. The solvent may be employed in an amount ranging from 10% to 75% and preferably 45% to 70% by weight to the gum base. A variety of traditional ingredients such as plasticizers or softeners such as lanolin, stearic acid, sodium stearate, potassium stearate, glyceryl triacetate or glycerine for example, natural waxes, petroleum waxes, such as polyurethene waxes, paraffin waxes and microcrystalline waxes may also be incorporated into the 25 additional gum base to obtain a variety of desirable textures and consistency properties. These individual materials are generally employed in amounts of up to 30% by weight and preferably in amounts of from 3% to 20% by weight of the final gum base composition. The chewing gum composition may additionally include the conventional additives of flavouring agents, colouring agents such as titanium dioxide; emulsifiers such as lecithin and glyceryl monostearate; 30 and additional fillers such as aluminium hydroxide, alumina, aluminium silicates, calcium carbonate, and talc and combinations thereof. These fillers may also be used in the gum base in various amounts. Preferably the amount of fillers when used will vary from 4% to 30% by weight of the final chewing gum. In the instance where auxiliary sweeteners are utilized, the present invention contemplates the inclusion of those sweeteners well known in the art, including both natural and artificial sweeteners. Thus, 35 additional sweeteners may be chosen from the following non-limiting list: sugars such as sucrose, glucose (corn syrup), dextrose, invert sugar, fructose, and mixtures thereof; saccharine and its various salts such as the sodium or calcium salt; cyclamic acid and its various salts such as the sodium salt; the dipeptide sweeteners such as aspartame; dihydrochalcone; glycyrrhizin; Stevia rebaudiana (Stevioside); and sugar alcohols such as sorbitol, sorbitoi syrup, mannitol or xylitol. Also contemplated as an additional sweetener 40 is the nonfermentable sugar substitute (hydrogenated starch hydrolysate) which is described in U.S. Reissue patent 26,959. Also contemplated is the synthetic sweetener 3,6 -dihydro -6 -methyl -1,1,2,3 - oxathiazin - 4 - one - 2,2 - dioxide particularly the potassium (Acesulfame-K), sodium and calcium salts thereof as described in DE—B— 2,001,017.7. Suitable flavourings include both natural and artificial flavours, and mints such as peppermint, 45 menthol, artificial vanilla, cinnamon, various fruit flavours, both individual and mixed, are contemplated. The flavourings are generally utilized in amounts that will vary depending upon the individual flavour, and may, for example, range in amounts of 0.5% to 3% by weight of the final composition weight. The colourants useful in the present invention, include the pigments such as titanium dioxide, that may so be incorporated in amounts of up to 1% by weight, and preferably up to 0.6% by weight. Also, the colourants may include other dies suitable for food, drug and cosmetic applications, and known as F.D. & C. dyes. The materials acceptable for the foregoing spectrum of use are preferably water-soluble. Illustrative examples include indigoid die, known as F.D. & C. Blue No. 2, which is the disodium salt of 5,5' - indigotindisulfonic acid. Similarly, the dye known as F.D. & C. Green No. 1, comprises a triphenylmethane 55 dye and is the monosodium salt of 4 - [4 - N- ethyl - p - sulfobenzylaminojdiphenylmethyiene] - [1 - (N -ethyl -N -p - sulfoniumbenzyl) -2,5 - cyclohexadienimine]. A full recitation of all F.D. &C. and D. & C. and their corresponding chemical structures may be found in the Kirk-Othmer Encyclopedia of Chemical Technology, in Volume 5, at Pages 857 — 884. Suitable oils and fats that are useable would include partially hydrogenated vegetable or animal fats, 60 such as coconut oil, palm kernel oil, beef tallow or lard. These ingredients are generally utilized in amounts with respect to the comestible product of up to 7.0% by weight, and preferably up to 3.5% by weight of the final product. It is generally accepted that as the required amount of active substance per structure gets smaller and/or less bad tasting, the task at arriving at an acceptable formulation becomes easier due to the greater es number of formulations available. Alternatively, extremely bad-tasting and/or high-dose drugs are difficult EP 0132 472 B1

to formulate into medicament/chewable tablets. The medicated product of the present invention overcomes these difficulties. The quantity of medicated product used may vary widely depending upon the particular medicament drug dosage. Amounts of medicament drug of 1 .0 to 200 mg per medicated dosage are useable dependant 5 upon the particular medicament drug. Naturally amounts of medicated product used will be higher depending on the therapeutic dosage required and amount of medicament drug adsorbed on the adsorbent material. Illustrative examples are described below. The usual dosage of dextromethorphan hydrobromide is between 10 and 30 mg per tablet. Incorporation of the medicated product into, for example, a candy base is not difficult because of its 10 melting point and solvent solubility. It is compatible with most flavours and is stable over a wide pH range. The dextromethorphan HBr when added as part of the medicated product avoids its bitter taste and flavouring difficulty. The usual dosage of d-phenylpropanolamine hydrochloride is 15 to 25 mg per tablet. The formulation is not difficult to flavour because of the absence of medicament after-taste. The usual dosage of 15 pseudophedrine hydrochloride is 15 to 60 mg per table. The usual dosage range of chloropheniramine maleate is 2 to 4 mg and lends itself easily to incorporation into a candy base. Naturally, the exact amount used will vary with the particular application and drug. The medicated product is generally present with the pharmaceutically acceptable carrier in an amount of from 1% to 60% by weight of the final composition. The exact amount will be dependent upon the 20 particular medicament drug and dosage required. The present invention is further illustrated by the following examples. All parts and percentages in the examples and throughout the specification and claims are by weight unless otherwise indicated.

Example 1 25 (Inventive runs 1 and 2) This Example demonstrates a method for preparing a dextromethorphan hydrobromide medicament product. To 30 grams water is mixed 6 grams dextromethorphan hydrobromide, at a water temperature around 90°C, until the drug was in solution. The solution was added to 60 grams magnesium trisilicate having a 30 mean specific surface area of 506.1 m2/g and mixed until a homogenous dispersion resulted, approximately 30 minutes. The mix was then oven dried at 70°C until a moisture content of below 15% was obtained. The product was then milled to prepare a white free-flowing powder containing 10% by weight dextromethorphan hydrobromide. An organoleptic evaluation test was performed on the product to determine the presence or absence of 35 bitterness. The product did not exhibit any bitterness or off taste when tested by a human panel of experts. The specific mean surface area of the materials were measured using the Quantasorb Sorption System (Quantachrome Corporation, N.Y.). The results are set forth in Table I. Figure 1 represents a photomicrograph of magnesium trisilicate used in this invention magnified 40 5000x. The Figure depicted shows a flake-like structure having extensive interstitial spaces. The flake-like character is evident throughout the entire structure and does not merely appear on the surface. No agglomeration or other spherical particles are noted. Figure 2 represents a photomicrograph of the medicated product containing dextromethorphan HBr adsorbate prepared in this inventive example, magnified 5000x. The Figure depicts a flake-like structure 45 having extensive interstitial spaces. The flake-like character is evident throughout the structure and does not merely appear on the surface. No agglomerates or other spherical particles are noted.

Example 2 (Comparative Runs A and B) so This Example demonstrates a dextromethorphan hydrobromide medicated product believed to be prepared by the process of Example 1 of U.S. Patent=US— A— 3,085,942. These materials are at least 10 years old. The process used broadly involved forming a mixture of dextromethorphan hydrobromide and magnesium trisilicate having an average particle size of 5 urn (microns) by dissolving the dextromethorphan hydrobromide in distilled water (80°C), and then pouring the 55 resulting solution onto the magnesium trisilicate. The resulting mixture is then thoroughly mixed by stirring to form a slurry. The solvent is then removed by spray-drying. A white free-flowing powder is obtained. An organoleptic evaluation test was performed on the adsorbate product to determine the presence or absence of bitterness. The product demonstrated acceptable characteristics in that it reduced the bitterness 60 of the drug. The mean specific surface area was measured as in Example 1, Run 1 with results set forth in Table I. Figure 3 represents a photomicrograph of the old magnesium trisilicate magnified 5000x. The Figure depicts an agglomerated product, with some interstitial spaces but absence of flake-like character throughout its structure. 65 Figure 4 represents a photomicrograph of the known medicated product containing dextromethorphan EP 0132 472 B1

HBr adsorbate magnified 5000x. The Figure depicts a smooth surfaced particle lacking interstitial spaces and flaked structure. TABLE I

Mean specific surface Run Material (m2/g area) Structure 10 Inventive 1 Magnesium 506.1 Flaked trisilicate (Figure 1)

Comparative A Old magnesium 415.1 Agglomerated 15 trisilicate (Figure 3)

Inventive 2 Medicated product 209.8 Flaked containing 10% (Figure 2) dextromethorphan HBr 20 Comparative B Medicated product 66.35 Smooth containing 10% (Figure 4) dextromethorphan HBr

25 Example 3 Inventive Runs 3, 4, 5 and 6 Comparative Runs C, D, E and F This Example compares the properties derived from various dextromethorphan HBr medicated products prepared by the process of Example 1 using different magnesium trisilicates from different 30 commercial sources. The results are set forth in Table II.

TABLE II Magnesium trisilicate 35 Mean specific surface Product area 40 Run taste (m2/g) Structure

Inventive 3 Good 441.8 Flaked

Inventive 4 Good 460.4 Flaked 45 Inventive 5 Good 564.2 Flaked

Inventive 6 Good — Flaked

50 Comparative C Bitter 181.8 Smooth surface

Comparative D Bitter 240.8 Smooth surface

Comparative E Bitter — — 55 Comparative F Bitter — —

Example 4 This example demonstrates a method for preparing a cold/sinus/asthma tablet formulation using a 60 medicated product prepared with chlorpheniramine maleate and pseudoephedrine HCI. The following ingredients are mixed in the order indicated:

65 EP 0132 472 B1

No. Ingredients Mg/tablet

1. Chlorpheniramine maleate — 10% medicated product (4.0 mg drug/tablet) 40.0 5 2. Pseudoephedrine HCI— 10% medicated product (60.0 mg drug/tablet) 600.0

3. Microcrystalline cellulose 37.3 10 4. Lactose 113.0

5. Modified cellulose gum 2.2 '5 6. Fumed silica 1.1

7. Stearic acid 1.3

8. MagnesiumMaanesium stearate 1.1 20 796.0

Procedure Screen #2, #7 and #8 through a 40 mesh sieve. Blend #1, #2, and #3 in V blender for 3 minutes. Add 25 #4, #5 and #6 to step #2 and blend for 17 minutes. Add #7 to step #3 and blend for 3 minutes. Add #8 to step #4 and blend for 5 minutes. Tablet to a hardness of 5.3 kg using 79 mm (5/16") standard concave punches.

Example 5 30 This example demonstrates a method for preparing an antihistamine tablet formulation using a medicated product prepared from pyrilamine maleate. The following ingredients are mixed in the order indicated.

No. Ingredients Mg/tablet 35 1. Pyrilamine maleate — medicated product (25 mg drug/tablet) 250.0

2. Microcrystalline cellulose 34.0 40 3. Lactose 136.8

4. Modified cellulose gum 2.0 45 5. Fumed silica ' 0.7

6. Stearic acid 0.5

7. Magnesium stearate 1.0 50 425.0

Procedure Screen #1,#6and #7 through 40 mesh sieve. Blend #1 and #3for3 minutes in V blender. Add #2, #4 55 and #5 to step #2 and blend for 17 minutes. Add #6 to step #3 and blend for 3 minutes. Add #7 to step #4 and blend for 5 minutes. Tablet using 79 mm (5/16") standard concave punches to a hardness of 5.5 kg.

Example 6 This example demonstrates a method for preparing a chewable cough tablet formulation using a 60 medicated product prepared with dextromethorphan HBr prepared by the process of Example 1. The ingredients are mixed in the order indicated:

65 EP 0 132 472 B1

No. Ingredients Mg/tablet

1. Dextromethorphan HBr — 10% medicated product (16 mg drug/tablet) 160.0 5 2. Candy base 2800.0

3. Frappe 320.0

10 4. Crystal sorbitol 120.0

5. Vegetable fat (palm kernal oil) 352.0

6. Sugar, granulated 200.0 w 7. Cherry flavor 40.0 4000.0

20 Procedure 1 49°C (300°F) candy base is cooled in a kettle to a temperature of 1 04 to 1 1 0°C (220 to 230°F). The frappe and sorbitol crystals are then mixed into the base to form a uniform mass. To the uniform mass is added with mixing the vegetable fat, color, and medicament adsorbate. Mixing is continued while the mass is cooled to 65°C (150cF). The sugar and flavor are combined with mixing and added to the previous blend. 25 Mixing is continued until a homogeneous mass is obtained. The product is removed from the kettle, cooled and then compressed into 4 g pieces. The tablet when chewed did not exhibit any medicinal after-taste due to the bitterness of the dextromethorphan HBr. Claims for the Contracting States: BE, CH, DE, FR, GB, IT, LI, LU, NL, SE

1. A medicated product comprising a magnesium trisilicate adsorbent and a medicament drug adsorbate chosen from antitussives, antihistamines, decongestants, alkaloid materials and mixtures thereof, the amount of drug adsorbate being in the range of from 1 % to 20% by weight of the medicated with 35 characterised in that the magnesium trisilicate adsorbent has a flake-like structure multiple least 440 more interstitial spaces and has, per gram, a surface area of at least 400 m2, preferably at m , preferably from 440 to 600 m2. 2. A medicated product according to Claim 1, wherein the medicament drug is selected from: antitussive materials, preferably dextromethorphan, dextromethorphan hydrobromide, noscapine, dextro- 40 carbetapentane citrate, chlophedianol hydrochloride and mixtures thereof, more preferable methorphan or dextromethorphan hydrobromides; antihistamine materials, preferably chlorpheniramine maleate, phenindamine tartrate, pynlamine maleate, doxylamine succinate, phenyltoloxamine citrate and mixtures thereof; decongestant materials, preferably phenylephrine hydrochloride, phenylpropanolamine hydro- 45 chloride, pseudoephedrine, ephedrine and mixtures thereof; and alkaloid materials, preferably codeine phosphate, codeine sulphate, morphine and mixtures thereof; and mixtures thereof. 3. A medicated product according to Claim 1 or 2, wherein the amount of medicament drug adsorbed of the medicated product. 50 onto the magnesium trisilicate is in the range from 5% to 15% by weight adsorbed -onto 4. A process for preparing a medicated product comprising a medicament drug a magnesium trisilicate, which process comprises: dissolving a medicament drug, chosen from antitussives, antihistamines, decongestants, alkaloid materials and mixtures thereof, in a solvent; admixing, with the dissolved drug, a magnesium trisilicate having a flake-like structure with multiple 55 m2 interstitial spaces, and which has, per gram, a surface area of at least 400 to prepare a mass having a homogeneous consistency which enables migration of the medicament drug within the interstitial spaces of the magnesium trisilicate; and recovering the medicated product. of solvent in the admixture containing the 6o 5- A process according to Claim 4, wherein the amount medicament drug and magnesium trisilicate adsorbent is in the range from 15% to 35% by weight, and wherein the admixture is granulated and dried so that the final solvent content of the admixture is in the range from 5% to 20% by weight. admixture the from 6. A process according to Claim 4, wherein the amount of solvent in the is in range from which the solvent is removed to form a paste. 65 30% to 60% by weight, whereby a slurry is prepared EP 0132 472 B1

7. A process according to Claim 6, wherein the paste is dried and recovered as a free flowing powder. 8. A process according to Claim 4, 5, 6 or 7, wherein the solvent is water. 9. A medicated composition comprising: a pharmaceutically acceptable carrier; and 5 in the range from 1% to 60% by weight of the final medicated composition, a medicated product according to Claim 1 containing (a) magnesium trisilicate adsorbent having a flake-like structure with multiple interstitial spaces, and which has, per gram, a surface area of at least 400 m2 and (b) in the range from 1 % to 20% by weight of the medicated product of a medicament drug adsorbate chosen from antitussives, antihistamines, decongestants, alkaloid materials and mixtures thereof. 10 10. A medicated composition according to Claim 9, wherein the pharmaceutically acceptable carrier is selected from a lozenge, a tablet, toffee, nougat, chewy candy or chewing gum.

Claims for the Contracting State: AT is 1. A process for preparing a medicated product comprising a medicament drug adsorbed onto a magnesium trisilicate, which process comprises: dissolving a medicament drug chosen from antitussives, antihistamines, decongestants, alkaloid materials and mixtures thereof, in solvent; admixing, with the dissolved drug, a magnesium trisilicate having a flake-like structure with multiple 20 interstitial spaces, and which has, per gram, a surface area of at least 400 m2, preferably at least 440 m2, more preferably from 440 to 600 m2, to prepare a mass having a homogeneous consistency which enables migration of the medicament drug within the interstitial spaces of the magnesium trisilicate; and recovering the medicated product. 2. A process for preparing a medicated product according to Claim 1, wherein the amount of 25 medicament drug adsorbed is in the range from 1 % to 20% by weight of the medicated product preferably in the range from 5% to 15% by weight of the medicated product. 3. A process according to Claim 1 or 2, wherein the amount of solvent in the admixture containing the medicament drug and magnesium trisilicate adsorbent is in the range from 15% to 35% by weight, and wherein the admixture is granulated and dried so that the final solvent content of the admixture is in the 30 range from 5% to 20% by weight. 4. A process according to Claim 1 or 2, wherein the amount of solvent in the admixture is in the range from 30% to 60% by weight whereby a slurry is prepared, from which the solvent is removed to form a paste. 35 5. A process according to Claim 4, wherein the paste is dried and recovered as a free flowing powder. 6. A process according to any preceding claim, wherein the solvent is water. 7. A process according to any preceding claim, wherein the medicament drug is selected from: antitussive materials, preferably dextromethorphan, dextromethorphan hydrobromide, noscapine, carbetapentane citrate, chlophedianol hydrochloride and mixtures thereof, more preferably dextro- ^o methorphan or dextromethorphan hydrobromides; antihistamine materials, preferably chlorpheniramine maleate, phenindamine tartrate, pyrilamine maleate, doxylamine succinate, phenyltoloxamine citrate and mixtures thereof; decongestant materials, preferably phenylephrine hydrochloride, phenylpropanolamine hydrochloride, pseudoephedrine, ephedrine and mixtures thereof; and 45 alkaloid materials, preferably codeine phosphate, codeine sulphate, morphine mixtures thereof; and mixtures thereof. 8. A process for producing a medicated composition which comprises combining together: a pharmaceutically acceptable carrier; and in the range from 1% to 60% by weight of the final composition, a medicated product containing (a) 50 magnesium trisilicate adsorbent having a flake-like structure with multiple interstitial spaces which has, per gram, a surface area of at least 400 m2 and (b) in the range from 1% to 20% by weight of the medicated product of a medicament drug adsorbate as obtained by the process according to Claim 1 the drug adsorbate being chosen from antitussives, antihistamines, decongestants, alkaloid materials and mixtures thereof. 55 9. A process for producing a medicated composition according to Claim 8, wherein the pharmaceutically acceptable carrier is selected from a lozenge, a tablet, toffee, nougat, chewy candy or chewing gum. Patentanspriiche fiir die Vertragsstaaten: BE, CH, DE, FR, GB, IT, LI, LU, NL, SE 60 1. Medizinisches Produkt umfassend ein Magnesiumtrisilikat - Adsorbens und ein Heilmittelwirkstoff - Adsorbat ausgewahlt aus Hustenmitteln, Antihistaminika, Dekongestionsmitteln, Alkaloid - Materialien und Mischungen davon, wobei die Menge des Wirkstoffadsorbats im Bereich von 1 bis 20 Gew.-% des medizinischen Produkts liegt; 65 dadurch gekennzeichnet, daft das Magnesiumtrislikat - Adsorbens eine flockenartige Struktur mit

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zahlreichen interstitiellen Raumen aufweist und pro Gramm einen Oberflachenbereich von zumindest 400 m2, vorzugsweise zumindest 440 m2, insbesondere von 440 bis 600 m2, aufweist. 2. Medizinisches Produkt nach Anspruch 1, worin der Heilmittelwirkstoff ausgewahlt ist aus: Hustenmitteln, vorzugsweise Dextromethorphan, Dextromethorphanhydrobromid, Noscapin, Carbeta- 5 pentan - citrat, Chlopedianolhydrochlorid und Mischungen davon, insbesondere Dextromethorphan oder Dextromethorphan - hydrobromiden; Antihistamin - Materialien, vorzugsweise Chlorpheniramin - maleat, Phenindamin - tartrat, Pyrilamin - maleat, Doxylamin - succinat, Phenyltoloxamin - citrat und Mischungen davon; Dekongestionsmittel, vozugsweise Phenylephrin - hydrochlorid, Phenylpropanolamin - hydrochlorid, 10 Pseudoephedrin, Ephedrin und Mischungen davon; und Alkaloid - Materialien, vorzugsweise Codeinphosphat, Codeinsulfat, Morphin und Mischungen davon; und Mischungen derselben. 3. Medizinisches Produkt nach Anspruch 1 oder 2, worin die Menge des auf dem Magnesiumtrisilikat adsorbierten Heilmittelworkstoffs im Bereich von 5 bis 15 Gew.-% des medizinischen Produkts liegt. 15 4. Verfahren zur Herstellung eines mediznischen Produkts umfassend einen auf einem Magnesiumtri- silikat adsorbierten Heilmittelwirkstoff, welches Verfahren umfaBt: Losen eines Heilmittelworkstoffs, welcher ausgewahlt ist aus Hustenmitteln, Antihistaminika, Dekongestionsmittel, Alkaloid - Materialien und Mischungen davon, in einem Losungsmittel; Mischen eines Magnesiumtrisilikats, welches eine flockenartige Struktur mit zahlreichen interstitiellen Raumen aufweist, und welches pro Gramm einen Oberflachenbereich von zumindest 400 m2 aufweist, mit dem gelosten Wirkstoff, um eine Masse mit einer homogenen Konsistenz, welche die Wanderung des Heilmittelwirkstoffs innerhalb der interstitiellen Raume des Magnesiumtrisilikats ermoglicht; herzustellen; und Gewinnung des medizinischen Produkts. 5. Verfahren nach Anspruch 4, worin die Menge des Losungsmittels in der den Heilmittelwirkstoff und 25 das Magnesiumtrisilikat - Adsorbens enthaltenden Mischung im Bereich von 15 bis 35 Gew.-% liegt, und worin die Mischung granuliert und getrocknet wird, sodalS der endgultige Losungsmittelgehalt der Mischung im Bereich von 5 bis 20 Gew.-% liegt. 6. Verfahren nach Anspruch 4, worin die Ldsungsmittelmenge in der Mischung im Bereich von 30 bis 60 Gew.-% liegt, wobei eine Aufschlammung hergestellt wird, aus der das Losungsmittel zur Bildung einer Paste entfernt wird. 7. Verfahren nach Anspruch 6, worin die Paste getrocknet wird und als freiflie&endes Pulver gewonnen wird. 8. Verfahren nach Anspruch 4, 5, 6 oder 7, worin das Losungsmittel Wasser ist. umfassend: 35 9. Medizinische Zusammensetzung einen pharmazeutisch akzeptablen Trager; und ein medizinisches Produkt nach Anspruch 1, im Bereich von 1 bis 60 Gew.-% der endgiiltigen medizinischen Zusammensetzung, welches umfaBt: (a) Magnesiumtrisilikat - Adsorbens mit einer flockenartigen Struktur mit zahlreichen interstitiellen Raumen, und welches pro Gramm einen Oberflachen- m2 und (b) Wirkstoffadsorbat, im Bereich von 1 bis 20 Gew.-% des jg bereich von zumindest 400 aufweist, medizinischen Produkts, welches ausgewahit ist aus Hustenmitteln, Antihistaminika, Dekongestions- mitteln. Alkaloid - Materialien und Mischungen derselben. 10. Medizinische Zusammensetzung nach Anspruch 9, worin der pharmazeutisch akzeptable Trager ausgewahlt ist aus einer Pastille, Tablette, einem Bonbon, einem Nougat, Kaukonfekt oder Kaugummi. 45 Patentanspriiche fur den Vertragsstaat: AT

1. Verfahren zur Herstellung eines medizinischen Produkts umfassend einen Heilmittelwirkstoff, welcher auf einem Magnesiumtrisilikat adsorbiert ist, welches Verfahren umfalSt: so Losen eines Heilmittelwirkstoffs, welcher ausgewahlt ist aus Hustenmitteln, Antihistaminika, De- kongestionsmitteln. Alkaloid - Materialien und Mischung davon, in einem Losungsmittel; Mischen eines Magnesiumtrisilikats, welches eine flockenartige Struktur mit zahlreichen interstitiellen Raumen aufweist, und welches pro Gramm einen Oberflachenbereich von zumindest 400 m2, vorzugsweise zumindest 440 m2, insbesondere von 440 bis 600 m2 aufweist, mit dem gelosten Wirkstoff, 55 um eine Masse mit einer homogenen Konsistenz, welche die Wanderung des Heilmittelwirkstoffs innerhalb der interstitiellen Raume des Magnesiumtrisilikats ermoglicht, herzustellen; und Gewinnung des medizinischen Produkts. 2. Verfahren zur Herstellung eines medizinischen Produkts nach Anspruch 1, worin die Menge des adsorbierten Heilmittelwirkstoffs im Bereich von 1 bis 20 Gew.-% des medizinischen Produkts, 60 vorzugsweise im Bereich von 5 bis 15 Gew.-% des medizinischen Produkts liegt. 3. Verfahren nach Anspruch 1 oder 2, worin die Menge des Losungsmittels in der den Heilmittelwirkstoff und das Magnesiumtrisilikat -Adsorbens enthaltenden Mischung im Bereich von 15 bis 35 Gew.-% liegt, und worin die Mischung granuliert und getrocknet wird, so dalS der endgultige Losungsmittelgehalt der Mischung im Bereich von 5 bis 20 Gew-% liegt. 65 4. Verfahren nach Anspruch 1 oder 2, worin die Menge des Losungsmittels in der Mischung im Bereich

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von 30 bis 60 Gew.-% liegt, wobei eine Aufschlammung hergestellt wird, aus der das Losungsmittel zur Biidung einer Paste entfernt wird. 5. Verfahren nach Anspruch 4, worin die Paste getrocknet und als freiflielXendes Pulver gewonnen wird. 5 6. Verfahren nach irgendeinem vorhergehenden Anspruch, worin das Losungsmittel Wasser ist. 7. Verfahren nach irgendeinem vorhergehenden Anspruch, worin der Heilmittelwirkstoff ausgewahlt ist aus: Hustenmitteln, vorzugsweise Dextromethorphan, Dextromethorphan - hydrobromid, Noscapin, Carbetapentan - citrat, Chlophedianol - hydrochlorid und Mischungen davon, vorzugsweise Dextro- w methorphan oder Dextromethorphan - hydrobromiden; Antihistamin - Materialien, vorzugsweise Chlor- pheniramin ■- maleat, Phenindamin -tartrat, Pyrilamin - maleat, Doxylamin -succinat, Phenyltoloxamin - citrat und Mischungen davon; Dekongestionsmaterialien, vorzugsweise Phenylephrin - hydrochlorid, Phenylpropanolamin - hydrochlorid, Pseudoephedrin, Ephedrin und Mischungen davon; und 15 Alkaloid - Materiaiien, vorzugsweise Codeinphosphat, Codeinsulfat, Morphin und Mischungen davon; und Mischungen davon. 8. Verfharen zur Herstellung einer medizinischen Zusammensetzung umfassend die Kombination: eines pharmazeutisch akzeptablen Tragers; und 20 eines medizinischen Produkts im Bereich von 1 bis 60 Gew.-% der endgultigen Zusammensetzung enthaltend (a) Magnesiumtrisilikatadsorbens mit einer flockenartigen Struktur mit zahlreichen interstitiellen Raumen, welches pro Gramm einen Oberflachenbereich von zumindest 400 m2 aufweist und (b) eines Heilmittelwirkstoff - Adsorbats im Bereich von 1 bis 20 Gew.-% des medizinischen Produkts, 25 welches ausgewahlt ist aus Hustenmitteln, Antihistaminika, Dekongestionsmitteln, Alkaloid - Materialien und Mischungen davon. 9. Verfahren zur Herstellung einer medizinischen Zusammensetzung nach Anspruch 8, worin der pharmazeutisch akzeptable Trager ausgewahlt ist aus einer Pastille, einer Tablette, einem Bonbon, einem Nougat, Kaukonfekt oder Kaugummi. 30 Revendications pour les Etats Contractants: BE, CH, DE, FR, GB, IT, LI, LU, NL, SE

1. Un agent pharmaceutique comprenant un adsorbant de trisilicate de magnesium et un medicament adsorbe choisi dans la classe des antitussifs, antihystamine, agents decongestionants, alcaloTdes et leurs 35 melanges, la quantite de medicament adsorbee etant comprise entre 1 et 20% par rapport au poids de I'agent pharmaceutique, caracterise en ce que I'adsorbant de trisilicate de magnesium presente une structure floconneuse renfermant de multiples espaces interstitiels, sa surface specifique par gramme etant au moins egale a 400 m2, de preference au moins egale a 440 m2 et etant de preference, notamment, comprise entre 440 et 600 m2. 40 2. Un agent pharmaceutique selon la revendication 1, dans lequel le medicament est choisi parmi les classes suivantes: produits antitussifs, de preference dextromethorphane, bromhydrate de dextromethorphane, noscapine, citrate de carbetapentane, chlorhydrate de chlophedianol et leurs melanges, de preference notamment dextromethorphane ou bromhydrate de dextromethorphane; antihistaminiques, de preference maleate de chlorpheniramine, tartrate de phenindamine, maleate de pyrilamine, succinate 45 de doxylamine, citrate de phenyltoloxamine et leurs melanges; agents decongestionants, de preference chlorhydrate de phenylephrine, chlorhydrate de phenylpropanolamine, pseudoephedrine, ephedrine et leurs melanges; et alcaloTdes, de preference phosphate de codeine, sulfate de codeine, morphine et leurs melanges; et des melanges des produits precedents. 3. Un produit pharmaceutique selon la revendication 1 ou 2, dans lequel la quantite de medicament so adsorbe sur le trisilicate de magnesium est comprise entre 5 et 15% en poids par rapport au poids de I'agent pharmaceutique. 4. Un procede de preparation d'un agent pharmaceutique comprenant un medicament adsorbe sur un trisilicate de magnesium, ce procede consistant a: — dissoudre un medicament choisi dans la classe des antitussifs, antihistaminiques, agents 55 decongestionants, alcaloTdes et leurs melanges dans un solvant; — melanger, avec le medicament dissous, un trisilicate de magnesium de structure floconneuse renfermant de multiples espaces interstitiels et dont la surface specifique par gramme est au moins egale a 400 m2 pour preparer une masse de consistance homogene permettant la migration du medicament au sein des espaces interstitiels du trisilicate de magnesium; et 60 — a recuperer I'agent pharmaceutique. 5. Un procede selon la revendication 1 , dans lequel la quantite de solvant dans le melange contenant le medicament et I'adsorbant a base de trisilicate de magnesium est comprise entre 15 et 35% en poids et dans lequel le melange est granule et seche de telle sorte que la teneur finale en solvant dans le melange soit comprise entre 5 et 20% en poids. 65 6. Un procede selon la revendication dans lequel la quantite de solvant dans le melange est comprise

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entre 30 et 60% en poids et dans lequel on prepare une suspension de laquelle on elimine le solvant pour •former une pate. 7. Un procede selon la revendication 6, dans lequel on seche la pate et on la recupere sous la forme de poudre s'ecoulant librement. 5 8. Un procede selon la revendication 4, 5, 6 ou 7, dans lequel le solvant est I'eau. 9. Une composition pharmaceutique comprenant: — un support pharmaceutiquement acceptable, et —une quantite comprise entre 1 et 60% en poids par rapport au poids de la composition pharmaceutique finale d'un produit pharmaceutique selon la revendication 1, contenant: 10 (a) un adsorbant a base de trisilicate de magnesium de structure floconneuse renfermant de multiples interstitiels et dont la surface specifique par gramme etant au moins egale a 400 m2; et espaces de (b) une quantite comprise entre 1 et 20% en poids de I'agent pharmaceutique d'un adsorbat medicament choisi dans la classe des antitussifs, antihystaminiques, agents decongestionants, alcalofdes et leurs melanges. 15 10. Une composition pharmaceutique selon la revendication 9, caracterisee en ce que le support pharmaceutiquement acceptable est choisi parmi les dragees, pastilles, caramels, nougats, confiseries a macher ou gommes a macher.

Revendications pour I'Etat Contractant: AT 20 1. Un procede de preparation d'un produit pharmaceutique comprenant un medicament adsorbe sur un trisilicate de magnesium, ce procede consistant a: — dissoudre un medicament choisi dans la classe des antitussifs, antihistaminiques, agents decongestionants, alcalofdes et leurs melanges dans un solvant; 25 — melanger, avec le medicament dissous, un trisilicate de magnesium de structure floconneuse renfermant de multiples espaces interstitiels et dont la surface specifique par gramme est au moins egale a 400 m2, de preference egale a 440 m2 et de preference, notamment, comprise entre 440 et 600 m2, pour medicament sein des preparer une masse de consistance homogene permettant la migration du au espaces interstitiels du trisilicate de magnesium; et 30 —a recuperer I'agent pharmaceutique. 2. Un procede de preparation d'un produit pharmaceutique selon la revendication 1, dans lequel la quantite de medicament adsorbe est comprise entre 1 et 20% par rapport au poids de I'agent pharmaceutique, de preference entre 5 et 15% en poids par rapport au poids de I'agent pharmaceutique. 3. Un procede selon la revendication 1 ou 2, dans lequel la quantite de solvant dans le melange 35 contenant le medicament et I'adsorbant de trisilicate de magnesium est comprise entre 15 et 35% en poids et dans lequel le melange est granule et seche de telle sorte que la teneur finale en soivant dans le melange soit comprise entre 5 et 20% en poids. 4. Un procede selon la revendication 1 ou 2, dans lequel la quantite de solvant dans le melange est comprise entre 30 et 60% en poids et dans lequel on prepare une suspension de laquelle on elimine le 40 solvant pour former une pate. 5. Un procede selon la revendication 4, dans lequel on seche la pate et on la recupere sous la forme de poudre s'ecoulant librement. 6. Un procede selon I'une quelconque des revendications precedentes dans lequel le solvant est I'eau. 7. Un procede selon I'une quelconque des revendications precedentes dans lequel le medicament est 45 choisi parmi les classes suivantes: produits antitussifs, de preference dextromethorphane, bromhydrate de dextromethorphane, noscapine, citrate de carbetapentane, chlorhydrate de chlophedianol et leurs melanges, de preference notamment dextromethorphane ou bromhydrate de dextromethorphane; antihistaminiques, de preference maleate de chlorpheniramine, tartrate de phenindamine, maleate de pyrilamine, succinate de doxylamine, citrate de phenyltoloxamine et leurs melanges; agents decon- 50 gestionants, de preference chlorhydrate de phenylephrine, chlorhydrate de phenylpropanolamine, pseudoephedrine, ephedrine et leurs melanges; et alcalofdes, de preference phosphate de codeine, sulfate de codeine, morphine et leurs melanges; et des melanges des corps precedents. 8. Un procede de preparation d'une composition pharmaceutique consistant a associer ensemble: — un support pharmaceutiquement acceptable, et 55 —une quantite comprise entre 1 et 60% en poids par rapport au poids de la composition pharmaceutique finale d'un agent pharmaceutique contenant: (a) un adsorbant a base de trisilicate de magnesium de structure floconneuse renfermant de multiples espaces interstitiels et dont la surface specifique par gramme est au moins egale a 400 m2; et (b) une quantite comprise entre 1 et 20% en poids de I'agent pharmaceutique d'un adsorbat de alcalofdes 60 medicament choisi dans la classe des antitussifs, antihystaminiques, agents decongestionants, et leurs melanges. 9. Un procede de preparation d'une composition pharmaceutique selon la revendication 8, dans lequel le support pharmaceutiquement acceptables est choisi parmi les dragees, pastilles, caramels, nougats, confiseries a macher ou gommes a macher. 65

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FIG. I

FIG. 2 EP 0 132 472 B1

FIG. 3

FIG. 4