TASTE MASKED ORAL COMPOSITIONS

Abstract: This invention is directed to the effective taste masking of a pharmaceutically active ingredient by granulation of the pharmaceutical active with an aqueous solution comprising a neutral methacrylic acid ester copolymer and a binder.

Description: TASTE MASKED ORAL COMPOSITIONS FIELD OF THE INVENTION The present invention relates to a granulation of a pharmaceutically active ingredient with an aqueous solution comprising a neutral methacrylic acid ester copolymer and a binder for the purpose of masking the taste of the pharmaceutically active ingredient. BACKGROUND OF THE INVENTION Most drugs are preferentially formulated as oral dosage forms due to the ease of administration and low cost of development. For children and the elderly who have difficulty in swallowing tablets, drugs are formulated as chewable or dispersible tablets, as dry powder for reconstitution or as liquid oral dosage forms. These formulations allow a greater exposure of the drug to the taste buds resulting in problems of patient compliance when highly bitter or unpleasant tasting drugs have to be administered. Various taste masking techniques are known in the art to address this problem of formulating bitter drugs. For drugs having subjectively minor bitterness, conventional taste masking techniques, such as, use of sweeteners, amino acids and flavoring agents are acceptable. However, for highly bitter drugs, complexation, microencapsulation, solid-dispersions and lipid entrapment are some of the techniques adopted for taste masking. Complexation and solid dispersion techniques with the help of ion exchange resins, polymers or other suitable agents, are very useful for taste masking. However, in many instances they require the use of organic liquids as reaction media/solvents and, therefore, raise regulatory concerns. Besides, in many instances, the amount of reactant for the drug to form proper taste-masked complex or solid dispersion, is very high. Microencapsulation of drug particles, including fine particle fluid bed coating, is a technology intenstive technique, requiring both sophistication in equipment and prior expertise of fine particle encapsulation. Numerous prior art documents disclose techniques of solvent based desolvation, interfacial condensation or denaturation, or particle coating in fluid bed coaters selecting any of the film formers from the short list of polymers commercially available. Again, the presence of organic solvents may generate regulatory and safety issues, particularly with respect to pediatric patients. Lipid entrapment often requires the use of spray congealing technique, which is quite sophisticated. Besides, for thermo-sensitive drugs, suspension in molten lipid during processing, may cause extensive drug degradation. Another taste masking technique which has been employed involves granulation of the bitter drug with polymers such that significant taste masking can be achieved. The granulated product may optionally be coated for achieving complete taste masking. Examples of this technique include that described in U.S. Patent No. 4,101 ,651. This patent describes a process for taste masking of bitter drugs for oral administration. The process involves dissolving ethyl cellulose at high concentration and adding the bitter drug, midecamycin into the solution. The midecamycin - ethyl cellulose suspension is kneaded followed by the addition of silicic acid anhydride to form a powder and granulating the powder using a solution of bitter taste masking substance in a fluidized bed granulator. Up to three times ethylcellulose by weight of the drug is used for taste masking. Apart from the use of large amounts of polymer, this method also suffers from the disadvantage of using organic solvents for granulation. U.S. Patent No. 4,916,161 describes a process for preparing taste masked tablets containing a foul tasting pharmaceutical agent, by wet granulating a dry particulate pre-granulation blend comprising the pharmaceutical active and hydroxypropyl methylcellulose phthalate with an aqueous granulating composition comprising a solution in which hydroxypropyl methyl- cellulose phthalate is at least partially soluble. This patent describes the use of an enteric polymer for taste masking and would be useful only when the drug is intended to be released in the distal portion of the gastrointestinal tract. U.S. Patent No. 5,188,839 describes a taste masked chewable tablet composition of cimetidine which comprises an effective amount of cimetidine and about 2-20% w/w relative to cimetidine of a copolymer of dimethyl ethyl methacrylate and neutral methacrylic acid esters (sold under the tradename of Eudragit ® E, Rohm GmbH) wherein the copolymer functions as a granulating and binding agent. This method suffers from the disadvantage that the copolymer is used as a non-aqueous solution. The use of organic solvent is discouraged in the present scenario due to an increased awareness of health and environmental hazards. U.S. Patent No. 5,047,319 describes a pharmaceutical granule composition comprising cimetidine and a taste masking and granulating agent, an ester of a polyhydroxy compound, wherein the polyhydroxy compound is a non-polymeric, non-aromatic hydrocarbon or carbohydrate having at least 2 hydroxyl groups per molecule. Numerous other examples are available which describe taste-masked pharmaceutical compositions, prepared by granulation process, using various polymers or waxes. The compositions described so far, generally require the use of large amount of polymers or waxes for effective taste-masking and use of organic solvents for granulation. Accordingly, none of the taste masking techniques heretofore described is completely satisfactory. DETAILED DESCRIPTION OF THE INVENTION The object of the present invention is to provide a process for taste masking of bitter drugs, wherein the drug is granulated with small to moderate amounts of a polymer without the use of any organic solvent. It gives obvious benefits with respect to cost effectiveness and environment friendly operations. It is also among the simplest of techniques for taste masking and is suitable for a wide range of very bitter drugs. In accordance with the present invention a taste masking formulation is described, wherein a pharmaceutically active ingredient is granulated with an aqueous solution comprising a neutral methacrylic acid ester copolymer and a binder, the resulting granules being optionally coated. The granules so prepared have an acceptable taste and have good dissolution characteristic in the simulated gastro-intestinal media. Polymer suitable for use in the present invention is a neutral copolymer of ethyl acrylate and methyl methacrylate also known as neutral methacrylic acid ester copolymer and sold under the trade name of Eudragit ® NE, as a 30% aqueous dispersion by Rohm GmbH of Germany. Said polymer is a compound of Formula I: where R is — COO.CH 3 . In accordance with the present invention, small to moderate amounts of the polymer composition is sufficient to mask the bitter taste of the drug. The dry weight of neutral methacrylic acid ester copolymer required is only 1- 40% by weight of the pharmaceutical active. It is preferred that the dry weight of the co-polymer should be between 5-30% by weight of the pharmaceutical active and, more preferably, between 8-25% by weight of the pharmaceutical active. The granules of the present invention are typically prepared by wet granulation method wherein an aqueous dispersion of the neutral methacrylic acid ester copolymer along with a binder is added to the powdered pharmaceutical ingredient, optionally mixed with other pharmaceutically acceptable excipients such as glidants and anti-adhesives and the resulting mixture is blended to form granules. The use of polymer dispersion alone as the granulating fluid creates problems during drying at elevated temperatures due to polymer softening. This problem has been overcome by the addition of a binder together with the polymer which gives additional hardness to the granules and facilitates the process of drying. It also helps in further taste- masking and modifying the drug release. Binder is selected from those used conventionally such as starch, acacia, tragacanth, gelatin, polyvinyl pyrrolidone, hydroxypropyl methylcellu- lose, hydroxypropyl cellulose, carboxymethyl cellulose, and hydroxyethyl cellulose. More preferably, the binder is chosen from amongst the commonly available carbohydrates such as sucrose, fructose and lactose. Most preferably, the binder employed is sucrose. The polymer and the binder are present in the ratio of 0.9: 0.1 to 0.1 :0.9 and more preferably, in the ratio of 0.3:0.7 to 0.7:0.3. Glidants/anti-adhesives are the agents, which are used to decrease or to avoid adhesion or the agglutination of particles during the coating process. Suitable substances are, for example, magnesium stearate, calcium stearate, calcium behenate, talc, colloidal silicic acid, stearic acid, precirol (mixture of moni-, di-, and triesters of palmitic and stearic acid with glycerol), hydrogenated cottonseed oil, hydrogenated ester oil and polyethylene glycol of differing molecular weights. Amounts of 0.1-150%, particularly of 5-100% by weight of the neutral methacrylic acid ester copolymer are preferably employed. The granules so obtained may optionally be coated for additional taste- masking of the product. Polymers conventionally used for coating include, the cellulosic polymers, vinyl polymers, polymethacrylate copolymers and enteric polymers. Film forming polymers which are useful, may include alkyl celluloses, such as, methyl or ethyl cellulose, hydroxyalkylcelluloses, such as hydroxypropyl cellulose or hydroxypropyl methylcellulose, vinyl polymers, such as polyvinyl acetate or polyvinyl acetate phthalate, polymethacrylate copolymers, available under the trade name Eudragit ® from Rohm GmbH, and mixture thereof. The coating polymer applied may be 1 to 50%, more preferably, 1 to 20% and most preferably, 3 to 15% by weight of the core. The granules so prepared, when ingested, release the incorporated medicinal actives slowly enough to avoid the perception of bitterness in the mouth, and thus allow the preparation of suitable unit dosage forms for oral administration. The new particles are particularly suited for processing to give chewable and dispersible tablets, granules for reconstitution, non-aqueous oily suspension, capsules, sprinkles and the like. The particles employed for above applications is about 50 microns to 1000 microns and average size of the particles about 250 microns. The following examples further illustrate the invention and are not intended to limit the scope of the invention. EXAMPLE 1 Table 1.1 Formula for granulating liquid: Table 1.2 Powder blend formula for granulation: Method : Granulating liquid was prepared by mixing the sugar with the polymer dispersion under stirring and diluting the same with the required amount of water. The granulating liquid so prepared was added to the drug powder blend and granulated. The granules were then dried at 60°C. Dried granules were sifted to give BSS#44/100 size fraction. The granules so prepared had good taste and desired release profile. EXAMPLE 2 Table 2.1 Formula for granulating liquid: Table 2.2 Formula for Powder blend for granulation: Method: Granulating liquid was prepared by dissolving Pharma Sugar into sufficient quantity of purified water and subsequently mixing it with polymer dispersion with continuous stirring. Resultant mixture was then mixed with the remaining amount of water and used after screening through BSS#85. Norfloxacin powder was mixed with Aerosil ® 200 (sifted through BSS #60) and the resulting powder mix was granulated with prepared granulating liquid. Granules were then dried at 60°C and sifted to give BSS #44/100 fraction. Dissolution and taste of the granules was good. EXAMPLE 3 Table 3.1 Formula for granulating liquid: Table 3.2 Formula for Powder blend for granulation: The dry powder blend was granulated with the prepared granulating liquid as described in Example 2, and the granules were dried at 60°C. The granules when evaluated for taste did not give any bitterness in the mouth. Dried and sized granules (BSS #44/100) were lubricated with 0.5% colloidal silicon dioxide and taste masking was further optimized by coating. 100g of the granules were coated with the coating composition as described in Table 3.3. The amount of methyacrylic acid copolymer applied was 10% by weight of the core. The coating was carried out in Glatt GPCG-1 equipment with a bed temperature not exceeding 32°C, fluidizing air velocity less than 2 m/sec and an atomization pressure of 2 bars. Table 3.3 Formula of the coating composition: The resultant granules had improved taste and were suitable for dispersion in suspension base. EXAMPLE 4 Table 4.1 Formula for granulating period: Table 4.2 Powder blend formula for granulation: Method: Granulating liquid was prepared by mixing the sugar with polymer dispersion under stirring for 30 minutes. The granulating liquid so prepared was added to the drug powder blend and granulated. The granules were then dried at 60°C. Dried granules were sifted to give BSS #25/60 size fraction. The granules so prepared had about 75% drug loading and had improved taste. 100g of the granules were coated with the coating composition as described in Table 3.3. The coating was carried out in Glatt GPCG-1 equipment with a bed temperature not exceeding 32°C, fluidizing air velocity less than 2m/sec and an atomization pressure of 2 bars. EXAMPLE 5 Table 5.1 Formula for granulating liquid: Method: Granulating liquid was prepared as described in Example 2. Dry powdered ingredients were sifted through BSS #60 and blended in a double cone blender for 20 minutes. Blended powder was granulated with the prepared granulating liquid and granules so obtained were dried at 60°C, followed by sizing to give BSS #44/100 fraction. The granules gave no bitter taste when kept in the mouth. EXAMPLE 6 Table 6.1 Formula for granulating liquid: Table 6.2 Powder blend formula for granulation: Method: Granulating liquid was prepared by mixing the sugar with polymer dispersion under stirring for 30 minutes. The dry powder blend was mixed and sifted through BSS #60. Blended powder was granulated with the prepared granulating liquid and granules so obtained were dried at 60°C, followed by sizing to give BSS #25/60 fraction. The granules when evaluated for taste, gave no bitterness in mouth. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Claims: WHAT IS CLAIMED IS: 1. A granulation of a pharmaceutically active ingredient is granulated with an aqueous solution comprising a neutral methacrylic acid ester copolymer and a binder, the resulting granules being optionally coated. 2. The granulation of claim 1 wherein the dry weight of neutral methacrylic acid ester copolymer is between 1-40% by weight of the pharmaceutical active. 3. The granulation of claim 2 wherein the dry weight of neutral methacrylic acid ester copolymer is preferably between 5-30% by weight of the pharmaceutical active. 4. The granulation of claim 3 wherein the dry weight of neutral methacrylic acid ester copolymer is most preferably present between 8-25% by weight of the pharmaceutical active. 5. The granulation of claim 1 wherein the binder is selected from sucrose, starch, acacia, tragacanth gum, gelatin, polyvinyl pyrrolidones, cellulosic polymers and mixtures thereof. 6. The granulation of claim 5 wherein the binder is most preferably sucrose. 7. The granulation of claim 1 wherein neutral methacrylic acid ester copolymer and the binder are present in the ratio of 0.9:0.1 to 0.1 :0.9. 8. The granulation of claim 7 wherein the neutral methacrylic acid ester copolymer and the binder are present in the ratio of 0.3:0.7 to 0.7:0.3. 9. The granulation of claim 1 wherein the composition contains other pharmaceutically acceptable excipients, including glidants and antiadhesive agents. 10. The granulation of claim 1 wherein taste-masked granules have a diameter of about 50 microns to about 1000 microns. 11. The granulation of claim 10 wherein taste-masked granules preferably have a mean diameter of less than 250 microns. 12. The granulation of claim 1 wherein coating polymer is present from 1- 50% by weight of the core. 13. The granulation of claim 12 wherein the coating polymer forms from 1 to 20% by weight of the core. 14. The granulation of claim 13 wherein the coating polymer forms from 3 to 15% by weight of the core.

Inventors: KHAR ROOP K, KUMAR MANOJ, MUKHERJI GOUR, SEN HIMADRI, KHAR, ROOP K., KUMAR, MANOJ, MUKHERJI, GOUR, SEN, HIMADRI
Applicants: KHAR ROOP K, KUMAR MANOJ, MUKHERJI GOUR, RANBAXY LAB LTD, SEN HIMADRI, KHAR, ROOP K., KUMAR, MANOJ, MUKHERJI, GOUR, RANBAXY LABORATORIES LIMITED, SEN, HIMADRI
Application year: 2000
Main classification: A61K9
IPC codes: A61K9