MXPA00003241A - Taste masked pharmaceutical compositions - Google Patents

Abstract

The present invention discloses the taste masking of drugs by wet granulating the drug with a microcrystaline cellulose compositions then spheronizing the granulation into spheres having a smooth uniform surface and a particle size in the range of 1 to 1000 microns.

Description

PHARMACEUTICAL COMPOSITIONS TO DISFRAZE THE TASTE DESCRIPTIVE MEMORY This invention relates to chewable pharmaceutical compositions in which the unpleasant taste of the pharmaceutically active agent is disguised by a physical form of the composition. More particularly, it relates to a simple, economical and effective method for preparing disguised flavor compositions, to said compositions, and to chewable tablets made in the same way, in which the active agent is mixed with a microcrystalline cellulose composition, granulated in wet, and forms into spheres with disguised flavor. Ibuprofen is an overuse painkiller and antibiotic that is not palatable enough to be used in chewable tablets for those people who do not ingest all solid dosage forms. Ibuprofen is very bitter. Flavoring agents such as the flavors of chocolate, anise, fruit, and the like have been proposed for use with drugs with bitter taste. However, flavoring agents are not safe concealers for ibuprofen since their bitter properties are very difficult to disguise to any appreciable extent. The most successful methods to disguise the flavor of ibuprofen have typically comprised coating the ibuprofen particles with a barrier or coating that will not dissolve in the mouth but will dissolve easily in gastric fluids. However, many coatings that resist breakage while chewing also tend to delay the bioavailability and / or release of the drug. A neutral spray therapeutic powder form of spray dried ibuprofen powder consisting essentially of 40% to 70% by weight of ibuprofen, 15% to 50% by weight of a cellulose material selected from ethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose is known. and mixtures thereof and 5% to 40% by weight of colloidal silica, from the US patent 4,835,187. The powder is obtained by spray-drying a suspension of colloidal silica in a solution of lower alkanol of the ibuprofen and the cellulose material. The procedure involves mixing two separate suspensions of ingredients, filtering them, then mixing the two filtrates and drying the combined suspension by spray. A more effective and simple procedure is desired to disguise the bitter taste of ibuprofen. The patent of E.U.A. 5,215,755 discloses chewable tablets and flavored granules disguised to do the same, wherein the granules were prepared by rotogranulation of the active with polyvinylpyrrolidone, sodium starch glycolate and sodium lauryl sulfate and coated with hydroxyethylcellulose or a mixture of hydroxyethylcellulose and hydroxypropylmethylcellulose . It is said that this coating achieves a beneficial balance of flavor concealment and bioavailability. Microcrystalline cellulose is described as a binder for the granules in the Compressed chewable tablets. Microcrystalline cellulose, an excipient commonly used primarily as a binder in compressed pharmaceutical tablets, alone or in combination with other excipients, flavoring agents, sweetening agents or other common tablet adjuvants, hitherto was known or thought to be ineffective disguise the flavor of ibuprofen or other active ingredients with similar bitter taste. Surprisingly, it has been found that microcrystalline cellulose excipient compositions easily disguise the unpleasant taste of ibuprofen and other similar pharmaceutically active agents having an unpleasant taste, when small amounts of microcrystalline cellulose compositions are wet granulated with the agent when they are formed into substantially spherical particles having a substantial smoothness, even on the surface and one size of average particle no greater than about 1000 microns. The microcrystalline cellulose compositions useful in the present invention are known to those skilled in the art and include microcrystalline cellulose per se, a product sold for example under the designation Avicel® PH-101 by FMC Corporation, Philadelphia, Pennsylvania.

Suitable microcrystalline compositions also include mixtures of microcrystalline cellulose with various hydrocolloids, advantageously compatible hydrophilic colloids including methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, sodium carboxymethylcellulose and gums such as guar gum, locust bean gum, konjac, xanthan, alginates, and combinations thereof. Suitably the weight ratio of microcrystalline cellulose to hydrocolloid, when used in combination, is on the scale of about 80:20 to about 99: 1, preferably 85:15 to 95: 5. Preferred microcrystalline cellulose compositions are coprocessed aggregates of microcrystalline cellulose and a hydrophilic hydrocolloid, preferably methylcellulose in which the weight ratio of microcrystalline cellulose to methylcellulose is from 99: 1 to about 90:10, preferably 97.5: 2.5 to about 92.5. : 7: 5 The preferred coprocessed aggregate of microcrystalline cellulose and methylcellulose is disclosed in PCT application WO93 / 12768 which was published on July 8, 1993 as a spheronizing agent useful for the production of more uniform spheres with high drug loading. The patent indicates that spheres loaded with drugs are useful as a substrate for coating and inclusion in controlled and / or sustained release drug delivery systems. The coprocessed aggregates of microcrystalline cellulose and methylcellulose are prepared in a known manner, as fully described in the PCT application identified above, which is incorporated herein by reference. In general, microcrystalline cellulose or an aqueous dispersion thereof is combined with an aqueous solution of hydrocolloid under high energy shear until the mixture ¿^ ^ ^ ^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ After the mixture is complete, the suspension is dried, preferably by spray drying, to produce a dry coprocessed aggregate of microcrystalline cellulose and hydrocolloid having significantly different properties from the separated components or from a simple two-component mixture. . The microcrystalline cellulose aggregate / methylcellulose is available for example as Avicel®, Grade of sphere from FMC Corporation, Philadelphia, Pa., As an aggregate containing 95% microcrystalline cellulose, 5% methylcellulose. In accordance with the present invention, disguised flavored pharmaceutical compositions are usefully obtained by the steps of: a) mixing together 70 to 90 parts by weight of a pharmaceutically active agent that is insoluble in water or sparingly soluble and has a Unpleasant taste; and from 10 to 30 parts by weight of a composition of microcrystalline cellulose excipient, to form a dry mixture of said agent and said excipient; b) adding to the resulting mixture, with agitation, from about 35 to 65 parts by weight of water per 100 parts by weight of mixture to form a wet granulation in which the water is equally distributed throughout, subsequently c ) to form substantially spherical particles granulated, flavored disguised with a smooth uniform surface and a particle size of up to 1000 microns, suitably in the range of about 100 to about 1000 microns, preferably about 250 approximately 900 micrometers. While the best method for practicing the invention contemplates the use of extrusion spheronization in step c), it is also very effective to form the soft particles in the form of a sphere using techniques such as high shear granulation or rotogranulation and the like, as indicated below in the document. Spheronization by extrusion includes the steps of dry blending the drug and excipients; wet granulate the dry mix; Extrude the wet granulation mass through a mesh with openings of about 0.5 to about 2.5 mm, preferably about 0.6 to 2.0, and still most preferably about 0.8 to about 1.5 mm to produce spaghetti-shaped filaments or cylindrically compacted strip; and spheronizing the filaments in a spheronizer. The latter is essentially a device equipped with a rotating or toothed rotating disc. Under the action of stirring / ligature of the rotating disc, the cylindrical filaments are broken into small segments that are smoothed and rounded to form the spheroids that are subsequently dried. For a more detailed description of the spheronization process, reference is made to "A New Technique for the Production of Spherical Particles" by A.D. Reynolds in Manufacturing Chemist, Aerosol News, V41, (June), p40-43, 1970. According to the extrusion spheronization modality, the neutral taste compositions are prepared by spheronization by extruding a composition containing, for example, from about 70 to about 90 parts by weight of the active agent, from about 10 to about 30, preferably from about 10 to about 15, parts by weight of a co-processed dry cellulose aggregate microcrystalline and methylcellulose or other microcrystalline composition or mixture, and optionally from about 4 to about 8, preferably from about 4.5 to about 7 parts by weight of dicalcium phosphate. The active agent and particles of the microcrystalline cellulose composition are first mixed dry until they are thoroughly mixed in a dry mix. The dry mix is added from about 35 to about 65 parts by weight of water per 100 parts of dry mix, and mixed until an extrudable granulated product is obtained. The granulated product is subsequently extruded through a mesh which preferably has openings of about 0.8 mm to about 1.5 mm. The extrusion products are subsequently placed in a spheronizer for a period of time sufficient to form spheres having smooth, uniform surfaces and preferably spheres having an average particle size diameter in the range of about 30 to about 800 microns. The spheres are then dried at an elevated temperature at a moisture content of less than 5%, preferably 3-5%, by any conventional drying means. According to a granulation mode, about 70 to about 85 parts by weight of the pharmaceutically active agent and from about 15 to about 30 parts by weight of the microcrystalline cellulose composition, mixed, or added to a mixture in a high shear granulator until the mixing is completed, then about 35 to about 50 parts by weight of water per 100 parts by weight of dry mix are fed to the granulator by gravity feed through a spray nozzle, increasing the speed of the blade and continuing the granulation until the resulting spheres have a smooth uniform surface, and preferably an average particle size on the scale of about 250 to about 900 microns. The resulting spheres can then be dried at an elevated temperature or by other suitable means. The present invention is particularly useful for producing neutral taste spherical compositions with drug loading too , for example on the scale of 70% to about 90% by weight of the resulting compositions. Thus, the aspect of the composition of this invention provides spherical particle compositions with neutral taste with an average particle size in the range of 300 to 800 microns comprising from about 70 to about 90 parts by weight of The pharmaceutically active ingredient comprises from about 10 to 30 parts by weight of microcrystalline cellulose composition, and optionally from 4 to 7 parts by weight of an alkaline earth metal phosphate, preferably a calcium phosphate such as dicalcium phosphate.

Those skilled in the art will appreciate that numerous pharmaceutically active agents, which need to be chewed rather than ingested as a compressed tablet, but having a taste that is unpleasant to patients, can disguise the taste in accordance with the method of this invention. In addition to having an unpleasant taste, the active agents prepared in accordance with this invention must be sufficiently insoluble in water to allow a not too long time in the mouth while chewing and before being ingested. Those skilled in the art will appreciate that in certain drugs the pH of the composition needs to be adjusted to achieve the desired degree of flavor concealment. Those skilled in the art will also appreciate that the present invention contemplates and includes the addition of other adjuvants normally used in the preparation of chewable tablets., including binders, sweeteners, flavorings and disintegrants, can be used in the tableting of spheres of the invention in chewable tablets. The invention also contemplates the use of the present invention for the preparation of spheres and chewable tablets containing said active ingredients such as: ibuprofen, ketoprofen, carprofen, calcium phenoprofen, naproxen and / or combinations thereof, either alone or in combination with other pharmaceutically active ingredients. The following examples illustrate the present invention with examples of the preparation of chewable ibuprofen and ketoprofen compositions of the invention and tablets made in the same way in which the unpleasant taste of the active substance is substantially reduced completely, making the tablets palatable and, for therefore, acceptable to the consumer, while they have virtually no adverse impact on the bioavailability of the drug in question. 5 EXAMPLE 1 Granulation and spheronization of Ibuprofen In the bowl of a Hobart mixer were placed 1700 grams of ibuprofen (Albermarle Corp.), 200 grams of Avicel® (Degree of Sphere, FMC Corporation), and 100 grams of dicalcium phosphate. 800 grams of deionized water was added to this dry mix.

Subsequently, the granulation was extruded through a sieve with 0.8 mm openings. The extrusion product was placed in a spheronizer operated at 800 rpm for 15 minutes. The resulting spheres were subsequently dried in an oven at 50 ° C for 12 hours. When these spheres were tested, the unpleasant taste of ibuprofen had been reduced by about 75-80% making the finished spheres acceptable and palatable. 20 The spheres were divided into two fractions of particle sizes. The first fraction passed through a standard No. 20 sieve of E.U.A. and not through a standard sieve number 30 of E.U.A., (590-840 microns), and the second fraction passes through a standard sieve number 35 ugly"...--,. -. • - a ^^ a = iESBSfcB-ifca and not through a standard 50 sieve (297-500 microns).

EXAMPLE 2 Chewable Ibuprofen Tablets The second fraction produced in example 1 (336.4 grams) and 357.2 grams of glyceryl monostearate (Myvaplex® 600, Eastman Chemical Co.) were placed in a twin-shell mixer and mixed for 10 minutes. At the end of this time, 285.8 grams of pregelatinised starch (Starch 1500, Colorcon), 857.4 grams of mannitol, 14.2 grams of aspartame (The NutraSweet Co.), 20 grams of citric acid, 20 grams of Avicel® CE (FMC Corporation) were added. ), 20 grams of ProSweet, 57.02 grams of Golden Punch durarome # 730104 (Firminich, Inc.), and 14.2 grams of Punch berry 65863317P (Firminich, Inc.) to the contents of the twin-shell mixer, and the mixture was continued for 15 additional minutes. Finally, 20 grams of magnesium stearate were added to the mixture, and mixed for an additional 5 minutes. Before adding each material to the mixer, it was passed through a standard No. 30 sieve of E.U.A. (ASTM E 11). This mixture was subsequently compressed into a tablet. The taste of ibuprofen was essentially undetectable when chewed and ingested.

. . ^ M ^ Mi *. ^, ^. . ^ - ^ m tr -liliÉBSMÉÉfiftifll ^ EXAMPLE 3 Wet Granulation of Ibuprofen In a high-shear granulator, 2250 grams of ibuprofen (Albemarle Corp.) and 750 grams of Avicel® (Degree of Sphere, FMC Corporation) were placed. The blade was operated at 300 rpm for three (3) minutes to mix the components, and the cross screw was operated at 1800 rpm. After this mixture was completed, 1147.5 grams of deionized water was fed to the granulator by gravity through a spray nozzle. When the water was completely added, the bowl was scraped, and subsequently the speed of the blade was increased to 600 rpm. Seven (7) minutes later the bowl was scraped again. The total time for this granulation was 44 minutes. The resulting spheres were subsequently dried in an oven at 50 ° C for twelve (12) hours. The particles made by this procedure were somewhat round with particle sizes ranging from less than 840 microns (20 mesh) to more than 250 microns (60 mesh). When these granules were tested, the unpleasant taste of ibuprofen was greatly reduced.

^^. ^^^. ^^ A.,. ^ ..,. .................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................. 4 Chewable Tablets Prepared from Wet Granulated Ibuprofen In a twin-shell mixer were placed 369.6 grams of the dry wet granulation of Example 3, 369.6 grams of glyceryl monostearate (Myvaplex® 600, Eastman Chemical Co.), 33.2 grams of aspartame (The NutraSweet Co.), 21.6 grams of apple cinnamon durarome # 860.310 / TD 05.91 (Firminich Inc.), and 27.6 grams of a Flavor of artificial special compound (Firminich Inc.). This mixture was mixed for 10 minutes after which 138.6 grams of pregelatinised starch (Starch 1500, Colorcon), 969.8 grams of granular mannitol, and 27.6 grams of interlaced sodium carboxymethyl cellulose (Accelerate ™, FMC Corporation) were added to the mixer. The mixture was continued for additional 10 minutes, and then 19.4 grams of magnesium stearate were added to the mixer. The mixture was completed in five minutes. Before adding each material to the mixer, it was passed through a standard No. 30 sieve of E.U.A. This mixture was subsequently compressed into a tablet. The particle size distribution of the The granulation that was used in this formulation was determined by using a fine sonic sieve, a vibratory cell of standard E.U.A. wherein each subsequent screen is of finer mesh than the one mentioned above. The amount of the product retained in each sieve provides the percentage of particles greater than the sieve, but less than the next higher sieve. The particles that have sizes in each mesh scale were: 48.23% > 297 microns (mesh> 50); 29.657% 177-297 microns (50-80 mesh); 5.39% 149-177 microns (80-100 mesh); 13.57% 74-149 microns (mesh 00-200); 3.17% 53-74 microns (200-270 mesh); and 5.00% < 53 microns (mesh <270). The low bulk density of this material was 0.6164 grams / ml. The water content of the granulation was 1.50%. The properties of the chewable tablets include tablet thickness (3.25 mm), hardness (2437.98 Kg), and disintegration time in purified water at 37 ° C, (184 seconds). All these measurements were taken in 10 tablets except the disintegration time which used six tablets. The unpleasant taste of ibuprofen was effectively disguised by using wet granulation together with other excipients.

EXAMPLE 5 Granulation and spheronization of ketoprofen In the bowl of a Powerex granulator were placed 2400 grams of ketoprofen, 420 grams of Avicel® (Degree of sphere, FMC Corporation), 75 grams of Methocel® A15LV (Dow Chemical Co.), 60 grams of sodium dibasic phosphate, and 15 grams of sodium lauryl sulfate. This dry mix was mixed for 5 minutes. A solution of 15 grams of Polysorbate 80 was prepared in 100 ml of deionized water which subsequently it was mixed with 1100 ml of deionized water. The granulator was operated at a blade speed of 150 rpm on the cross screw at 1800 rpm. The aqueous solution was pumped to the granulator at 75 ml / minute. The granulation was subsequently extruded through a sieve with 1 mm openings. The extrusion product was placed in a spheronizer operated at 800 rpm for 15 minutes. The resulting spheres were subsequently dried in an oven at 65 ° C for 1 hour. When these spheres were tested, the unpleasant taste of ketoprofen had been reduced by about 75-80%, making the finished spheres acceptable and palatable. 10 EXAMPLE 6 Ketoprofen chewable tablets The spheres that were produced in Example 5 (92.6 grams) and 15 296.2 grams of concentrated glyceryl monostearate (Myvaplex® 600, Eastman Chemical Co.) were placed in a twin-shell mixer and mixed for 10 minutes. At the end of this time, 148 grams of 1,500 starch (Colorcon), 888.6 grams of mannitol, 42 grams of aspartame (The NutraSweet Co.), 296.2 grams of Avicel® PH-102 (FMC 20 Corporation), 12 grams of Firmenich were added. Special Compound (a flavoring agent), 71 grams of tuti fruti flavor, 29.6 grams of croscarmellose sodium (Ac-Di-Sol®, FMC Corporation), 100 grams of Avicel® CE-15 to the contents of the twin shell mixer, and the mixing was continued during _tt_ __ e ^ _ ^ _ ^ _ ^ _ ^ _ ^ _ ^ __ a __ ^ _ ^ | ^ _ 15 additional minutes. Finally, 24 grams of magnesium stearate was added to the mixture and mixed for an additional 5 minutes. Before adding each material to the mixer, it was passed through a standard 30 mesh U.S. Subsequently, this mixture was compressed using a Stokes B-2 tablet press coupled with a 1.1 mm flat-faced round tool. An upper compression force of 1063.12 kg and a lower compression force of 982 kg were used. The tablets produced had an average weight of 0.3376 grams and a thickness of 4.27 mm. The taste of ketoprofen was essentially disguised due to the effectiveness of the spheronized formulation combined with the other excipients that were included in the formulation of the final tablet.

EXAMPLE 7 Granulation and spheronization of ibuprofen using methylcellulose and microcrystalline cellulose In a Hobart mixing bowl, 750 grams of ibuprofen, 12.5 grams of Methocel® A15LV (Dow Chemical Co.), and 237 grams of microcrystalline cellulose (Avicel® PH-101, 20 FMC Corporation) were dry blended for 5 minutes. Subsequently, water (450 grams) was added to the contents of the bowl while mixing continued for a period of at least 15 minutes. The wet granulation produced in this way was subsequently extruded through a screen with 0.8 mm openings to a feed speed of 50 rpm and an agitator speed of 25 rpm. The extrusion material was placed in a spheronizer for 2 to 5 minutes at a speed of 500 rpm with a minimum purge air pressure. The collected spheres were dried in an oven at 50 ° C for 12 hours. When these spheres were tested, the taste concealment was compared to that which occurred in example 1.

EXAMPLE 8 Granulation and spheronization of ibuprofen using microcrystalline cellulose In a mixing bowl of Hobart, 750 grams of ibuprofen and 250 grams of microcrystalline cellulose (Avicel®PH-101, FMC Corporation) were mixed dry for 5 minutes. Water (600 grams) was then added to the contents of the bowl while mixing for a period of at least 15 minutes. The wet granulation produced in this way was subsequently extruded through a sieve with openings measuring 0.8 mm at a feed speed of 50 rpm and a stirrer speed of 25 rpm. The extrusion product was placed in a spheronizer for 2 to 5 minutes at a speed of 500 rpm with a minimum purge air pressure. The collected spheres were dried in an oven at 50 ° C for 12 hours. When these spheres were tested, the taste concealment was comparable to that produced in example 1.

Claims (9)

NOVELTY OF THE INVENTION CLAIMS

1. A method for preparing a pharmaceutical composition for disguising the flavor to compress it into pharmaceutically chewable tablets comprising: a) mixing together 70 to 90 parts by weight of a pharmaceutically active agent that is insoluble in water or only slightly soluble and has an unpleasant taste with about 10 to 30 parts in

The weight of a microcrystalline cellulose excipient composition to form a dry mixture of said agent and said excipient; b) adding to the mixture, with agitation, 35 to 65 parts by weight of water per 100 parts by weight of dry mix to form a wet granulation in which the water is equally distributed throughout; c) later form the 15 wet granulation into substantially spherical particles to disguise the taste with a smooth uniform surface and a particle size on the scale of 100 to 1000 microns. 2. The process according to claim 1, further characterized in that the wet granulation is extruded through 20 of a sieve with apertures of 0.5 mm to 2.5 mm and spheronized in a spheronizer to form spheres with disguised flavor.

3. The process according to claim 1, further characterized in that the wet granulation is prepared and formed in spheres using a high shear granulator to form spheres with disguised flavor.

4. The process according to claim 1, further characterized in that the microcrystalline cellulose excipient is selected from a group consisting of a) microcrystalline cellulose, b) microcrystalline cellulose and a compatible hydrophilic hydrocolloid in which the ratio by weight of microcrystalline cellulose to hydrocolloid is in the range of 99: 1 to 90:10, and c) a dry coprocessed aggregate of microcrystalline cellulose and a compatible hydrophilic hydrocolloid, in which the weight ratio of microcrystalline cellulose to Hydrocolloid is from 99: 1 to approximately 90:10.

5. The process according to claim 4, further characterized in that the hydrocolloid is methylcellulose.

6. Pharmaceutical compositions for disguising the flavor prepared by the process according to claim 1, 2, 3, 4 or 5, comprising from 70% to 90% by weight of the pharmaceutically active agent selected from ibuprofen and ketoprofen.

7. Disguised taste chewable tablets comprising a pharmaceutically effective amount of the composition according to claim 6 in admixture with compatible excipients and adjuvants.

8. The taste chewable tablets disguised according to claim 7, further characterized in that the pharmaceutically active agent is ibuprofen. ^^ tó __ ^ __ ^ _ ^ __ ^ _ ^ __ g __ ^ _ faith __ ^ __ ^ _ _ «_ ^ __ ^ | ^ __ ^ __ ^ __ ^ i ^ __ ^ _ ^ | _¡_ _§

9. Chewable taste tablets disguised according to claim 8, further characterized in that the pharmaceutically active agent is ketoprofen. ^^ Sg ^^ __ ^ __ ^ __ and __ ^ __ ^ _ ^ l _ ^ _ ^ _ iiS _ ^ _ ^ _ | ^ _ ^ _ ^ _ ^ _ ^ _ ^ _ ^ _ ^ _ ^ _ ^ _ ^ _ ^ _ ^ _ _ ^ _ ^ _ ^ fe »nfo na»:. i¡a