DRUG IN COMBINATION WITH FLAVOR MASKING AGENT AND METHOD FOR MAKING SAME

Abstract: According to this invention various hygroscopic malflavored drugs can be proceeded by a unique wet granulated process wherein a slurry of the drug in water is dried in combination with colloidal silicon dioxide and, in a particularly preferred embodiment microcrystalline cellulose with the colloidal silicon dioxide absorbing onto the drug particles. The result is a protective coating of silicon dioxide which masks unpleasant taste and odor and also reduces the adhesive of the granulation onto the punch faces used in the manufacture of the granules. By adsorbing silicon dioxide on the particulate surface of the malflavored hygroscopic drug, the drug becomes not only easier to handle but the unpleasant tastes and/or odors are masked making the final product more susceptible to proper patient compliance.

Description: Drugs are most commonly administered orally and as such must be placed in a suitable form for oral ingestion. Not only must the drug be adapted to be delivered at desirable dosage levels but, at times, depending upon the nature of the drug, must be protected from rapid moisture absorption. Certain hygroscopic drugs have distinctly unpleasant tastes and odors. In addition hygroscopic and waxy drugs present processing problems during tabletting and encapsulation. Examples of drugs which possess one or more of these properties are oxtriphylline, procainamide HCl, gemfibrozil, disopyramide phosphate, fenoprofen calcium, atenolol, piracetam, carbamazepine, tetracycline HCl, oxytetracycline HCl, rifamprin, lincomycin HCl, clindamycin HCl, cefaclor, cefadroxil, cephrabine, thiamine HCl, ascorbic acid, acetylsalicylic acid, methocarbamol, methyldopa, sulindac, desipramine HCl, ranitine HCl, ethionamide, divalproex sodium, meprobamate, captopril, and aminophylline. These drugs as well as other hygroscopic unpleasant tasting drugs are known for purposes of this specification as malflavored drugs and, because of their off flavors and difficult handling, provide problems both for the drug manufacturer as well as in the area of patient compliance in taking proper amounts. Silicon dioxide is an ingredient commonly used in the tablet art as an aid to tablet processing. Low levels of silicon dioxide usually below 2% are generally employed. European Patent Application 108,218 by James Michael Dunn et al describes the formation of constant release rate tablets of water soluble drugs employing from 0.5 to 3 rate percent of fumed silicon dioxide as a lubricant. U.S. Patent 4,536,511 issued to Wolfgang Fisher et al, discloses a drug specific combination including levels of silica and cellulose below 1% evidently to aid binding and flow characteristics in a wet granulation system for the drug muzolimine. U.S. Patent 4,526,777 issued to Cheryl D. Blume et al discloses the combination of two dry granulations including microcrystalline cellulose as a binding and disintergrant with syloid as a flow enhancer again in precedingly low levels. Patents issued to James M. Dunn, namely U.S. 4,461,759; 4,522,804; 4,521,402; and 4,521,401 disclose 0.4 to 3.09 % silicon dioxide in combination with hydrogenated vegetable oil and an acrylic acid polymer. U.S. Patent 4,609,675 issued to Robert M. Franz discloses using silicon dioxide at a 1% level for dry granulation of ibuprofen. U. S. Patent 4, 478, 819 issued to Hercelin, teaches silicon dioxide used in forming extruded granules. U.S. Patent 4,442,086 issued to James M. Quinlan discloses the use of silica as a glidant at levels not greater than 0.05%. U.S. Patent 4,415,547 teaches the use of silica dioxide as a dusting powder for pellets which are subsequently compressed into tablets. U.S. Patent 3,592,927 issued to Maximillan Koffier discloses a calcium pantothenate composition which is produced in dry free flowing form by the inclusion of silicon dioxide during its manufacturer at a level below 5%. U.S. Patent 4 338 311 to Ralph A. Heasley discloses a stable solid formulation of choline salicylate and hydrophilic silicon dioxide in rather high amounts (more than 25% by weight), wherein the SiO₂ is used as a tabletting aid. In addition, European Patent Application 167,191 discloses the inclusion of silicon dioxide as an aid to direct compression of tablets. European Patent Application 136,100 discloses the combination of sucralfate with microcrystalline cellulose and colloidal silicon dioxide as a suspending agent at extremely low levels. Summary of the Invention According to this invention various unpleasant flavored drugs can be processed by a unique wet granulation process wherein a slurry of the drug in water is dried in combination with colloidal silicon dioxide and, in a particularly preferred embodiment microcrystalline cellulose is used with the colloidal silicon dioxide adsorbing onto the drug particles. By unpleasant flavored drugs, for purposes of this invention, the term is defined as drugs which are unpleasant tasting and/or smelling and/or are hygroscopic and/or tacky. The result is a protective coating of silicon dioxide which masks unpleasant taste and odor, decreases moisture absorption, and also reduces the adhesiveness of the granulation onto the punch faces used in the manufacture of the granules. By adsorbing silicon dioxide on the particulate surface of the malflavored hygroscopic drug, the drug becomes not only easier to handle but the unpleasant tastes and/or odors are masked making the final product more susceptible to proper patient compliance. Detailed Description of the Invention Levels of silicon dioxide generally from 5 % by weight and up to 20 % by weight of the combination of the drug and the other solid components are necessary to provide a noticeable masked effect. The drug used in the combination is usually present at a level of 30 to 70% by weight with other commonly used granulating and tabletting aids being added as necessary or desired as within the skill of the art to provide a total dry weight combination of 100%. Particularly preferred is the addition of a drying adjunct with microcrystalline cellulose being especially preferred at levels up to about 45 % preferably 5 to 45 % by weight of the combination. Microcrystalline cellulose also serves as a filler/binder which helps form particularly suitable granules and aids in the compression of the granules during tabletting. As mentioned above, this invention involves a unique wet granulation process wherein colloidal silicon dioxide and preferably other excipients, especially microcrystalline cellulose are adsorbed onto particles of a particular hygroscopic malflavored drug. Once the granulation process is completed the mixture is dried in an oven, milled and tabletted to an appropriate sized tablet. Lubricants and disintegrants may be added to the formulation prior to tabletting as well as suitable coloring agents as is well known in the art. Tablets with excellent compressibility and over 20 kg hardness may be achieved at relatively low tabletting forces. The same process is useful for preparing granules to be placed in hard gelatin capsules. In addition, film coating can be used to provide an additional moisture barrier. Drugs which particularly benefit from the process of this invention are 3-phenoxypyridine monosulfate pramiracetam, and gemfibrozil. When these drugs are used in combination with silicon dioxide the difficulties inherent in their manufacture are substantially diminished and the malflavor of these drugs is also minimized. (Pramiracetam is (N-[2-]Bis(1-methylethyl)amino]ethyl]-2-oxo-1-pyrolidine acetamide, sulfate (1:1)). Examples of the process of this invention follow with two specific drugs used. It is to be understood that the examples are merely illustrative of malflavor drugs. The ingredients used in the first example are set forth in the table below. EXAMPLE 1 A sample was prepared as indicated by first milling the drug with colloidal silicon dioxide through a 1B screen utilizing a hammer mill. Separately, sodium lauryl sulfate is added to water in a planetary mixer and then the aqueous mixture is mixed with the combination of silicon dioxide and 3 phenoxypyridine monosulfate. Crospovidone is then added to aid in disintegration. Colloidal silicon dioxide is then added and mixed for about 5 minutes followed by the addition of microcrystalline cellulose. The granulation is then dried in an oven at 50°C to a moisture content of less than 0.5% and further processed by milling through a 1B screen and then combined with calcium stearate, crospovidone and talc. Tablets are formed by compressing 1140 mg of the mixture to a hardness generally between 18 and 20 Kgm using an ellipital punch. The tablet is then film coated with a mixture of about 4% coat containing hydroxypropylmethylcellulose.

Claims: Claims for the following Contracting States: AT, BE, CH, DE, FR, GB, IT, LI, LU, NE, SE In combination, a particulate drug and colloidal SiO₂ adsorbed on said drug particles in an amount of 5 to 20 % by weight of the combination as a protective coating. The combination of claim 1 wherein the drug is present at at a level of 30 to 70 % by weight of the combination. The combination of claims 1 to 2 wherein an adjunct is added to further dry the formulation. The combination of claim 3 wherein the adjunct is microcrystalline cellulose. A tablet formed from the combination of claim 1 to 4 comprising at least one member selected from the group consisting of excipients, disintegrants and glidants. A process for the production of a solid drug dosage form according to claims 1 to 5 comprising: a) forming a slurry of the drug in water b) adsorbing the colloidal SiO₂ on the surface of the drug to form a protective coating; and c) drying the combination. The process of claim 6 wherein microcrystalline cellulose is added with the SiO₂. The process of claim 6 wherein examples are milled and tabletted. 3-phenoxypyridine monosulfate in combination with SiO₂ according to claim 1 to 5. Pramiracetam in combination with SiO₂ according to claims 1 to 5. Gemfibrozil in combination with SiO₂ according to claims 1 to 5. The combination of claim 9 to 11 wherein microcrystalline cellulose is present at a level of up to 45 % by weight of the combination. Use of a combination according to claims 1 to 4 and 9 to 12 to minimize the unpleasant flavor effects of a drug. Use of a combination according to claims 1 to 4 and 9 to 12 to minimize moisture absorption and adhesiveness of a drug. Claims for the following Contracting States: ES, GR A process for the production of a solid drug dosage form comprising: a) forming a slurry of the drug in water b) adsorbing 5 to 20 weight% of colloidal SiO₂ on the surface of the drug to form a protective coating; and c) drying the combination. A process according to claim 1 wherein the drug is present at a level of 30 to 70 % by weight of the combination. A process of claims 1 to 2 wherein an adjunct is added to further dry the formulation. A process of claim 3 wherein the adjunct is microcrystalline cellulose. A process according to claims 1 to 4 wherein at least one member selected from the group consisting of excipients, distintegrants and glidants is added. The process of claim 4 wherein microcrystalline cellulose is added with the SiO₂. The process of claims 1 to 6 wherein examples are milled and tabletted. The process of claims 1 to 7 wherein 3-phenoxypyridine monosulfate is added in combination with SiO₂. The process of claims 1 to 7 wherein pramiracetam is added in combination with SiO₂. The process of claims 1 to 7 wherein gemfibrozil is added in combination with SiO₂. The process of claims 8 to 10 wherein microcrystalline cellulose is added at a level of up to 45 % by weight of the combination.

Inventors: BOTZOLAKIS, JOHN E., HARRIS, MICHAEL R., NESBITT, RUSSELL U.
Applicants: WARNER-LAMBERT COMPANY
Application year: 1989
Main classification: A61K9
IPC codes: A61K47, A61K31, A61K33, A61K9