United States Patent
`
`[19]
`
`[11] Patent Number:
`
`6,099,865
`
`Augello et al.
`
`[45] Date of Patent:
`
`Aug. 8, 2000
`
`US006099865A
`
`[54] CROSCARMELLOSE TASTE MASKING
`
`FOREIGN PATENT DOCUMENTS
`
`[75]
`
`Inventors: Michael Augello, Marlboro, N.J.;
`Sheila M. Dell, New Hope, Pa.;
`George E. Reier, Somerset, N.J.;
`H0Wa1‘d J- Stamawy Bridgewatera N~—l~;
`Lynn M‘ DiMemm0’ Hamilton’ NJ’
`
`5091150
`
`4/1994
`
`Japan .
`
`Primary Exa/m'rzer—Tliuriiiaii K. Page
`Assistant Examiner—William E. Benston
`
`Assignee: FMC Corporation, Philadelphia, Pa.
`
`Afiornex Agmé Or Firm4MC COIPOHMOH
`
`Appl. No.: 09/330,445
`
`Filed:
`
`Jun. 11, 1999
`
`Related US. Application Data
`Provisional application No. 60/091,996, Jul. 87 1998'
`
`Int. Cl? ....................................................... A61K 9/62
`U.S. Cl.
`.......................... 424/494; 424/489; 424/464;
`424/495; 424/470
`Field 01' Search ................................... .. 424/489, 464,
`424/470, 468, 458
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`[57]
`
`ABSTRACT
`
`The present invention describes the use of croscarmellose
`d.
`t
`tbitt
`-1
`t.
`t.
`t
`i
`th t
`so ium o coa
`.1 cr as ing ac ivc agcn
`in a manner
`a
`Wlll mask the bitter taste of these materials, taste masked
`pharmaceutical compositions in which the particles of phar-
`. H
`.
`d
`.h
`H
`‘“*‘‘’‘’‘”‘‘’a V *‘‘’‘‘V‘’ age“‘ are "Om" ““ "r°S“*‘”“" 05*’
`sodium,
`taste masked pharmaceutical
`tablets made
`therefrom, in which the rapid disintegration of tablets that is
`imparted by croscarmellose sodium is preserved, and to a
`method for preparing such coated particles by preparing
`.
`.
`.
`.
`them in a fluidized bed coating process.
`
`5,874,418
`
`2/1999 Stella et al.
`
`............................. .. 514/58
`
`12 Claims, N0 Drawings
`
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`

`
`6,099,865
`
`1
`CROSCARMELLOSE TASTE MASKING
`
`2
`These findings are particularly surprising and unexpected in
`view of the fact that croscarmellose sodium has not hereto-
`
`This application claims benefit of Provisional Applica-
`tion Ser. No. 60/091,996 filed Jul. 8, 1998.
`
`fore been used as a taste masking agent.
`BRIEF SUMMARY OF THE INVENTION
`
`FIELD OF THE INVENTION
`
`The present invention relates to the use of croscarmellose
`sodium to coat bitter-tasting active agents in a manner that
`will mask the bitter taste of these materials. More partic11-
`larly tl1e present
`invention relates to a particulate taste
`masked pharmaceutical composition in which particles of a
`pharmaceutically active agent are coated with croscarmel-
`lose sodium. It also relates to taste masked pharmaceutical
`tablets made therefrom, in which the rapid disintegration of
`tablets that is imparted by croscarmellose sodium is pre-
`served. The invention also provides a method for preparing
`the particulate taste masked pharmaceutical compositions.
`BACKGROUND OF THE INVENTION
`
`Croscarmellose sodium has been widely used as a dis-
`persant and disintegrant in the pharmaceutical industry. It is
`known to have been used as a “super disintegrant” for
`pharmaceutical
`tablets where rapid disintegration and/or
`dispersion is required to render pharmaceutical actives
`promptly physiologically available. Croscarmellose is typi-
`cally used in such applications in combination with other
`pharmaceutically acceptable adjuvants such as binders,
`lubricants, dispersants, surface active agents and the like, all
`of which are well known to those skilled in the art of
`
`formulating pharmaceutically active agents.
`Bitter tasting pharmaceutically active agents are particu-
`larly difficult to render palatable when placed in tableted
`dosage forms. Much research and many techniques have
`been employed in the art to effectively mask the taste of
`bitter tasting pharmaceuticals without retarding the physi-
`ological availability of the bitter tasting active ingredients.
`Well known methods for
`taste masking generally have
`involved coating of the particles of the active ingredient
`and/or the tablet containing such active ingredient, with
`various coating materials or combinations of coating mate-
`rials many or most of which have limited water solubility
`and are therefore applied from organic media. However, on
`the one hand, the more water soluble such coatings are, the
`less effective they are in taste masking, and on the other hand
`the less water soluble they are the more they tend to retard
`the physiological availability of the active ingredient.
`Moreover, in order to achieve both rapid disintegration and
`taste masking it has been necessary to use both a coating and
`a disintegrant or super disintegrant, such as croscarmellose
`sodium, in the tablet formulation. This is extremely costly in
`requiring both a coating step and the addition of relatively
`costly disintegrants. Accordingly there is a continuing need
`for less costly and more effective methods for achieving
`taste masking while at
`the same time assuring prompt
`physiological availability of the active ingredient. It
`is a
`further advantage of the present invention that the coating
`solution employed herein is entirely aqueous, so that there is
`no organic residue left in the coated particles.
`It has now been found that these and other objects of the
`invention can be achieved by utilizing croscarmellose
`sodium as both a coating agent and as a disintegrant, thereby
`eliminating the need for use of separate coating and disin-
`tegrants in tableting formulations. It has further been found
`that particle size of the active ingredient and the method
`used to coat the active both play an important role in the
`ability to use croscarmellose sodium to serve both functions.
`
`in accordance with a first aspect of this
`Accordingly,
`invention there is provided a particulate taste masked pl1ar-
`maceutical composition comprising a substrate which con-
`sists essentially of particles of a pharmaceutically active
`agent having an objectionably bitter taste coated with a taste
`masking amount of croscarmellose sodium, the amount of
`the coating being in the range of 10 to 50 percent by weight
`of the substrate.
`
`In accordance with a second aspect of this invention there
`is provided a method for masking the bitter taste of a
`pharmaceutically active agent without separate coating and
`disintegrant agents which comprises:
`(a) fluidizing in fluidized bed coating apparatus a sub-
`strate having a particle size in the range of 50 to 500
`microns consisting essentially of an objectionably bit-
`ter tasting pharmaceutically active agent;
`(b) Spraying into said fluidized bed an aqueous solution of
`croscarmellose sodium an amount in the range of 10 to
`50 percent by weight of said substrate; and
`(c) Recovering a taste masked coated pharmaceutical
`composition consisting essentially of said pharmaceu-
`tically active agent coated with a taste-masking amount
`of croscarmellose sodium.
`In yet another embodiment of the invention there is
`provided a taste masked pharmaceutical dosage form com-
`prising a tablet for oral administration consisting essentially
`of a therapeutically effective amount of the particulate
`composition of the coated active ingredient described above
`in admixture with one or more compatible pharmaceutically
`acceptable adjuvants,
`in which croscarmellose sodium
`serves as both taste masking agent and dispersant, without
`the need for additional dispersants or coating agents or steps.
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`In accordance with the first aspect of this invention, the
`particulate taste masked pharmaceutical composition com-
`prises particles of a pharmaceutically active agent having an
`objectionably bitter taste in which the particles of pharma-
`ceutically active agent are coated with a taste masking
`amount of croscarmellose sodium. For purposes of this
`invention, in order to effectively taste mask the pharmaceu-
`tical composition described above, it is generally necessary
`to use slightly more croscarmellose sodium for purposes of
`taste masking than is normally employed when employing
`croscarmellose sodium as a super disintegrant for pharma-
`ceutical tablets. In this invention, however, it is used to coat
`particles of the bitter tasting pharmaceutical active ingredi-
`ent rather than as a simple additive or excipient which is
`blended with the active agent or ingredient and other adju-
`vants in the tableting formulation. As a coating material, it
`is employed in an amount in the range of 10 to 50 percent,
`preferably in the range of 15 to 28 percent, and most
`preferably from about 18 to about 25 percent by weight of
`the substrate to which it
`is applied as a taste masking
`coating. At these levels and when applied as a coating as
`described below, it serves the dual function of acting as a
`taste masking agent and as a super disintegrant for tableted
`dosage forms.
`In addition to the use of appropriate amounts of croscar-
`mellose sodium as a coating for the active ingredient, the
`
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`
`6,099,865
`
`3
`particle size of the active ingredient is also important in
`achieving adequate taste masking. As shown in the examples
`below the taste masking efficacy of croscarmellose sodium
`is dramatically reduced when the particle size of the sub-
`strate is below about 60 microns and/or when a large
`percentage of the substrate has a fine particle size. Accord-
`ingly it is important to the present invention that the active
`ingredient which forms the substrate to be coated by the
`croscarmellose sodium have a particle size in the range of 50
`to 500 microns, that not more than about 1 percent of the
`particles have a particle size smaller than 60 microns and/or
`that not more than about 1.5 percent of the substrate particles
`have a particle size less than about 125 microns. Accord-
`ingly it is preferred to use a substrate which is in crystalline
`form rather than in a powdered form. It is also important in
`the coating process to control
`the inlet
`temperature to
`maintain a temperature below the melting point of the
`substrate to be coated to that the substrate does not melt
`during the coating process.
`In order to increase adherence croscarmellose to the
`
`active ingredient particles, a binder may be added to the
`coating solution or suspension. Suitable binders include
`ethylcellulose, hydroxypropylmethyl cellulose,
`methylcellulose, polyvinylpyrrolidone, or other binders con-
`ventionally employed in pharmaceutical preparations.
`In
`general these binders are used in the present invention at
`very low levels simply to assure that the croscarmellose
`coating strongly adheres to the particulate pharmaceutically
`active agent. Though these ranges may vary with the par-
`ticular binder or formulation, they are suitably employed at
`levels in the range of about 4 up to about 10 percent by
`weight of the coated particulate product, including active
`ingredient and coating solids, but excluding water present in
`the coating solution, preferably in the range of about 4 to
`about 6 percent by weight. These levels are substantially
`below the level at which these binders are normally used for
`other purposes in some pharmaceutical preparations, for
`example as enteric coatings or taste masking agents.
`Advantagcously, plasticizcrs may also be included in the
`coating solutions or suspensions of the present invention for
`the purpose of plasticizing thc cthylccllulosc suflicicntly to
`provide it with sufficient flexibility and hardness to prevent
`the coating from being abraded or destroyed when the
`coated particles are subsequently handled in processing
`equipment and/or compressed into tableted dosage forms.
`Suitable plasticizers include polyethylene glycol having a
`molecular weight in the range of 200 up to about 8000,
`propylene glycol, glycerin, glycerin triacetate,
`triethylcitrate, dibutylsebacate (DBS), or other conventional
`plasticizers for pharmaceutical preparations. The amount of
`plasticizer employed may vary over a wide range depending
`on the plasticizer used and the binder employed in the
`formulation,
`it is generally preferred to utilize sufficient
`plasticizer to provide from about 0.2 to about 3 percent by
`weight of the total particulate product.
`In accordance with the process aspect of this invention, a
`fluidized bed coating apparatus is required to spray an
`aqueous solution or suspension of croscarmellose sodium, as
`described above,
`into a fluidized bed of the particulate
`pharmaceutical active substrate.
`Fluidized bed coating machines are manufactured by
`numerous companies. One, a Wurster coater, is essentially a
`bowl in which the substrate to be coated is placed and air is
`blown from the bottom to create the fluid condition of the
`
`solid. In the Wurster coater, a spray nozzle is placed 11nder
`the fluidized bed, providing a bottom spray which coats the
`fluidized particles. A preferred method of coating the par-
`
`4
`ticles utilizes a fluidized bed which operates similarly to the
`Wurster apparatus, but has a spray nozzle located above the
`fluidized bed, providing a downwardly directed spray which
`coats the particles. One manufacturer of a top spray fluidized
`bed coater is the Niro Company. The top spray appears to
`provide a better coating and actually increases the average
`particle size of the coated particles of active agent. A
`common characteristic of all fluidized bed coating opera-
`tions is that these are batch operations.
`Thus the preferred process aspect of this invention is a
`coating process in which a granular substrate is directly
`coated. Although wet granulation techniques have been
`attempted in an effort to increase particle size of the active
`ingredients with and without croscarmellose sodium prior to
`fluidized bed coating with croscarmellose sodium,
`these
`techniques were not found to be as effective to achieve taste
`masking as simply coating the crystalline materials and
`involved extra processing steps rendering them less cost
`effective. Thus, while such additional steps are contemplated
`as within the scope of this invention, they are not considered
`the best mode for practicing the invention.
`The substrate can be any solid, preferably crystalline,
`pharmaceutical active ingredient which has a bitter taste that
`requires taste masking. Examples of suitable substrates
`include acetaminophen, ibuprofen, ketoprofen, other similar
`members of this class of nonsteroidal anti-inflammatory
`agents, guiafenesin, dextromethorphan, chlorophenirimine,
`and bromophenirimine. The active ingredient may be highly
`water soluble or have limited water solubility. Those skilled
`in the art of taste masking will appreciate that numerous
`other pharmaceutical actives which have a particularly
`objectionable bitter taste may also be taste masked in
`accordance with the present invention.
`It will be appreciated by those skilled in the coating and/or
`taste masking art that some experimentation may be required
`with each machine and/or active ingredient, to ascertain the
`optimum particle size distribution of coated particulate
`pharmaceutically active material. It will also be appreciated
`that once this has been ascertained for a particular coating
`machine and/or pharmaceutical active, the product could be
`screened to remove particles smaller than a particular
`dimension, without departing from the spirit and scope of
`this invention. This material passing through an appropri-
`ately sized screen could be utilized in applications where
`taste masking of the active is not required, and thus make the
`process even more cost effective.
`When the coated substrate is incorporated into the final
`tablet formulation, the amount of croscarmellose sodium in
`the tableted formulation will generally be in the range of
`about 1—10% by weight of the finished tablets. Since this is
`at or slightly above the range at which croscarmellose
`sodium is normally employed as a disintegrant in tablets or
`tableting formulations its dual functionality as a coating and
`taste masking agent and as a disintegrant for tablets formed
`from the coated composition of this invention will be readily
`apparent to those skilled in the formulation and taste mask-
`ing art.
`The product of the process is preferably a free flowing
`particulate granular material comprising the particulate
`pharmaceutically active agent having a coating comprising
`croscarmellose sodium, a binder, and optionally a plasti-
`cizer. The product may be compressed as such into taste-
`masked tableted dosage forms, or may be blended with
`tableting additives conventionally used in the formulation of
`pharmaceutical tablets then compressed into a tableted dos-
`age forms. Such additives include, for example, fillers such
`
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`
`6,099,865
`
`5
`as microcrystalline cellulose and/or various gums, sweetners
`such as Aspartame®, Prosweet®, mannitol, sucrose, or other
`sweetners, Ilow aids such as magnesium stearate, and other
`additives conventionally employed in preparing tableting
`formulations.
`
`The following examples further illustrate the practice of
`the present invention. These examples are for illustration
`purposes only and are not intended to limit the scope of the
`invention except as described elsewhere in the specification
`or claims. In the accompanying examples all percentages are
`percent by weight unless otherwise indicated. In each of the
`examples the percentage of taste masking was determined
`by submitting a sample to 15 to 20 people who tasted the
`sample and compared it with a control sample and reported
`whether on not in their opinion the test sample effectively
`masked the bitter taste of the active ingredient. The percent-
`age number given in the example is thus a reflection of the
`percentage of tests in which the test sample was judged
`effectively taste masked.
`
`Example 1 describes the preferred method of coating
`crystalline acetaminophen with a croscarmellose solution
`using a top spray and a fluidized bed. Example 2 shows the
`preparation of tablets and results of the taste masking
`produced by the coatings of Example 1 and relates the
`effectiveness to particle sizes shown in Example 1. Example
`3, shows the effectiveness of taste masking in which the total
`coated material is utilized and compared with a fraction of
`the particles of the same material larger than 149 microns.
`Also, there is the comparison with a commercial, solvent-
`coated acetaminophen. Example 4 is indicative of the lower
`limit of croscarmellose sodium which must be used to
`
`provide effective taste masking. Example 5 is a comparative
`example to show the effect of no coating at all. Example 6
`uses the same commercial, solvent-coated, crystalline
`acetaminophen that was used in Example 3, and is included
`to show the greatly reduced friability of using croscarmel-
`lose sodium-coated acetaminophen in a rapid tablet press as
`compared with the current commercial material. Examples 7
`and following demonstrate the coating process of the present
`invention with ibuprofen, guiafenesin and acetaminophen
`utilizing a binder and plasticizer in the coating solution.
`
`EXAMPLE 1
`
`In a fluidized bed coater with a bowl insert was placed 1.0
`Kg of crystalline acetaminophen. A slurry of 250 grams of
`croscarmellose in 3322 grams of water, a 7% solids slurry,
`was prepared. This slurry was top-sprayed onto the fluidized
`bed of acetaminophen, requiring approximately 2 hours to
`complete the coating process. During the coating process the
`inlet temperature and the outlet temperature were main-
`tained at 80° C. and 36° C., respectively. The percentages of
`particles of various sizes were determined by passing the
`product through a stack of sieves, each one flner than the one
`above it. This is Example 1A for which the particle size
`distribution is shown in Table 1. Two additional identical
`
`coatings were made except that double the amount of each
`material was used. These are Examples 1B and 1C. Sieve
`analysis data for each of these materials are shown in Table
`1 also. A comparative sieve analysis of the substrate crys-
`talline acetaminophen is also included in Table 1.
`
`6
`
`TABLE 1
`
`Particle size
`
`Crystalline
`
`Example
`
`1B
`
`1C
`
`(microns)
`>500
`297-500
`210-297
`125-210
`62-125
`<62
`
`APAP
`0.53%
`66.44%
`32.59%
`0.44%
`0
`0
`
`1A
`9.17%
`87.13%
`2.68%
`0.46%
`0.56%
`0
`
`EXAMPLE 2
`
`In a large twin shell blender were placed 253.2 grams of
`acetaminophen crystals which had been sprayed with a
`slurry of croscarmellose sodium (Example 1A) and 189.9
`grams of Avicel® CE-15 (microcrystalline cellulose/guar
`gum, 85/15, sold by FMC Corporation, Philadelphia, Pa.
`19103). These components were blended for 10 minutes. At
`the end of this period, 113.9 grams of Avicel PH-102, 25.3
`grams of Aspartame® powder, and 25.3 grams of
`ProSweet® were added to the blender, and mixing was
`continued for an additional 10 minutes. Next, 384.9 grams
`of granular mannitol was added to the blender, followed by
`10 more minutes of mixing. Finally, 7.6 grams of magne-
`sium stearate which had been passed through a 30 mesh US
`Standard screen was added and blended for 3 minutes. This
`
`composition was compressed on a Bztablet press operated at
`39 RPM and fitted with round, 9.525 mm (0.375 inch)
`diameter, standard convex tooling. The upper compression
`force was in the range of 900 to 1100 Kg and the lower
`compression force averaged 1000 Kg. The average weight,
`thickness, and hardness of these tablets were, respectively,
`0.413 gram, 5.56 mm (0.2189 inch), and 7.64 Kp. Friability
`after 4 minutes was 0.0239%, and tablet disintegration time
`in 37° C. water without stirring was approximately 2 min-
`utes. Taste masking was approximately 95%. This is
`Example 2A. Two additional
`identical formulations,
`Examples 2B and 2C, were prepared, respectively, from
`acetaminophen coated with croscarmellose sodium in
`Examples 1B and 1C. Formulation 2B was taste masked less
`than Formulation 2A and exhibited some of the character-
`istic bitterness of acetaminophen. Formulation 2C was taste
`masked to a lesser degree than either Formulation 2A and
`exhibited minor bitterness of the acetaminophen. The tablet
`properties of these tablets are shown in Table 2.
`
`TABLE 2
`
`2A
`
`900-1100
`n
`1000
`~2
`0.0239%
`
`Example
`
`2B
`0.384
`4.37
`5.94
`
`NR“
`NR
`<1
`0.125%
`
`2C
`
`NR
`NR
`<1
`0.252%
`
`Tablet Property
`
`Weight (gram)
`Thickness (mm)
`Hardness (Kp)
`Compression force
`
`Upper (Kg)
`Lower (Kg)
`Disintegration (min)
`Friability (%)
`“NR- not recorded
`
`EXAMPLE 3
`
`Using the procedure of Example 2, 25.27 grams of
`acetaminophen powder which had been coated with a slurry
`
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`6,099,865
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`7
`of croscarmellose sodium in a Wurster fluidized bed using a
`bottom spray was placed in a twin shell blender. The weight
`ratio of acetaminophen powder to croscarmellose sodiLLrn
`was 85:15. Then, 16.13 grams of Avicel® CE-15
`(microcrystalline cellulose/guar gum, 85/15, sold by FMC
`Corporation, Philadelphia, Pa. 19103) was added to the
`blender and blended for 10 minutes. At the end of this
`
`period, 5.10 grams of Avicel PH-102, 4.84 grams of Aspar-
`tame® powder, 0.54 gram of Enhance® and 1.07 grams of
`ProSweet® were added to the blender, and mixing was
`continued for an additional 10 minutes. Next, 46.24 grams
`of granular mannitol was added to blender, followed by 10
`more minutes of mixing. Finally, 0.8 gram of magnesium
`stearate which had been passed through a 30 mesh US
`Standard screen was added and blended for 3 minutes. This
`
`composition was compressed on an F tablet press fitted with
`round, 9.525 mm (0.375 inch) diameter, standard convex
`tooling. The average weight,
`thickness, and hardness of
`these tablets were, respectively, 0.3496 gram, 4.44 mm
`(0.1749 inch), and 3.44 Kp. Friability after 4 minutes was
`1.0%, and tablet disintegration time in 37° C. water without
`stirring was less than 30 seconds. Taste masking was
`approximately 85%. This is Example 3A.
`
`A portion of the coated acetaminophen powder used to
`prepare Example 3A was passed through a 100 mesh U.S.
`Standard screen, and the portion remaining on the screen,
`i.e., the particles that were larger than 149 microns, was used
`in an identical formulation to Example 3A to prepare the
`tablets of Example 3B. Taste masking was improved to 90%
`by using only the larger coated particles.
`
`A comparative formulation was prepared in which com-
`mercial coated, crystalline acetaminophen (Eurand
`America)
`replaced the croscarmellose-coated acetami-
`nophen. The Eurand material is a solvent-coated material,
`making slight adjustments necessary in the weights of other
`components to provide the same amount of acetaminophen
`per tablet. This comparative formulation is Example 3C
`which provided 95% taste masking of the acetaminophen.
`The formulations of Examples 3A, 3B, and 3C are shown in
`Table 3, and the corresponding tablet properties are shown
`in Table 4.
`
`TABLE 3
`
`Formulation
`Components
`Coated APAP
`Avicel PH-102
`Mannitold
`Avicel CE-15
`Aspartame
`Pro Sweet
`Enhance
`Mg stearate
`
`3A
`(grams)
`25.27“
`5.10
`46.24
`16.13
`4.84
`1.07
`0.54
`0.82
`
`Example
`3B
`(grams)
`25 .27”
`5.10
`46.24
`16.13
`4.84
`1.07
`0.54
`0.82
`
`3C
`(grams)
`24.25“
`5.18
`46.87
`16.35
`4.90
`1.09
`0.54
`0.82
`
`“Cr0scarmellose sodium-coated acetaminophen powder comprising par-
`ticles larger and smaller than 149 microns
`bCr0scarmellose sodium-coated acetaminophen powder in which all par-
`ticles were larger than 149 microns
`“Coated acetaminophen (Eurand America)
`“Granular mannitol
`
`8
`
`TABLE 4
`
`Tablet Property
`
`Weight (gram)
`Thickness (mm)
`Hardness (Kp)
`Disintegration (min)
`Friabiiity (%)
`
`3C
`
`Example
`
`3B
`
`0.3614
`4.45
`4.67
`<0.5
`0.83
`
`3A
`
`.
`
`EXAMPLE 4
`
`In a large twin shell blender were placed 228.5 grams of
`acetaminophen powder which had been coated with a slurry
`of croscarmellose sodium in a Wurster fluidized bed appa-
`ratus using a bottom spray. The ratio of acetaminophen to
`croscarmellose sodium was 94:6. Also added to the blender
`
`were 107.5 grams of Avicel® CE-15 (microcrystalline
`cellulose/guar gum, 85/15, sold by FMC Corporation,
`Philadelphia, Pa. 19103), 32.2 grams of Aspartame®
`powder, 26.9 grams of ProSweet®, 21.5 grams of fruit
`punch flavor, and 2.69 grams of anhydrous citric acid. These
`components were blended for 10 minutes. At the end of this
`period, 53.8 grams of Avicel PH-102 and 518 grams of
`granular mannitol were added to the blender, and mixing
`was continued for an additional 5 minutes. Finally, 8.0
`grams of magnesium stearate which had been passed
`through a 30 mesh US Standard screen was added and
`blended for 5 minutes. This composition was compressed on
`a 512 tablet press fitted with round, 9.525 mm (0.375 inch)
`diameter, standard convex tooling. There was very slight
`taste masking exhibited by these tablets.
`EXAMPLE 5
`
`In a twin shell blender were placed 64.35 grams of
`acetaminophen crystals and 60.33 grams of Avicel® CE-15
`(microcrystalline cellulose/guar gum, 85/15, sold by FMC
`Corporation, Philadelphia, Pa. 19103). These components
`were blended for 10 minutes. At the end of this period, 36.48
`grams of Avicel PH-102, 6.04 grams of Aspartame®
`powder, and 6.04 grams of ProSweet® were added to the
`blender, and mixing was continued for an additional 10
`minutes. Next, 120.83 grams of granular mannitol was
`added to blender, followed by 10 more minutes of mixing.
`Finally, 2.4 grams of magnesium stearate which had been
`passed through a 30 mesh US Standard screen was added
`and blended for 3 minutes. This composition was com-
`pressed on a B2 tablet press operated at 39 RPM and fitted
`with round, 9.525 mm (0.375 inch) diameter, standard
`convex tooling. The upper compression force averaged
`1900.5 Kg. The average thickness and hardness of these
`tablets were, respectively, 4.32 mm (0.1699 inch), and 5.38
`Kp. Tablet disintegration time in 37° C. water without
`stirring was less than 1 minute. There was no taste masking,
`and the tablets were described as having a bitter, metallic
`taste with a long—lasting aftertaste.
`EXAMPLE 6
`
`In a large twin shell blender were placed 253.2 grams of
`solvent-coated commercial acetaminophen (Eurand
`America) and 189.9 grams of Avicel® CE-15
`(microcrystalline cellulose/guar gum, 85/15, sold by FMC
`. Corporation, Philadelphia, Pa. 19103). These components
`were blended for 10 minutes. At the end of this period, 113.9
`grams of Avicel PH-102, 25.3 grams of Aspartame®
`
`TEVA EXHIBIT 1021
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`RBP_TEVA05022489
`
`TEVA EXHIBIT 1021
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`6,099,865
`
`9
`powder, and 25.3 grams of ProSweet® were added to the
`blender, and mixing was continued for an additional 10
`minutes. Next, 384.8 grams of granular mannitol was added
`to blender, followed by 10 more minutes of mixing. Finally,
`7.6 grams of magnesium stearate which had been passed
`through a 30 mesh US Standard screen was added and
`blended for 3 minutes. This composition was compressed on
`a B2 tablet press operated at 39 RPM and fitted with round,
`9.525 mm (0.375 inch) diameter, standard convex tooling.
`The average weight, thickness, and hardness of these tablets
`were, respectively, 0.3921 gram, 4.39 mm (0.173 inch), and
`6.53 Kp. The friability of these tablets was 2.84%, and the
`disintegration timc in 37° C. water without stirring was lcss
`than 1 minute. An upper compression force of at least 1500
`Kg was required to provide tablets having the properties
`described above. There was, however, approximately 95%
`taste masking of the bitter taste of acetaminophen.
`EXAMPLE 7
`
`Alarge beaker was charged with 2464.5 grams of deion-
`ized water which was stirred with a propeller stirrer. To this
`water was added 185.5 grams of croscarmellose sodium.
`Mixing was continued for one ho11r
`to fillly hydrate the
`croscarmellose sodium. In a second container, 193 grams of
`30% ethylcellulose solution (Aquacoat® ECD, FMC
`Corporation) and 14.8 grams of polyethylene glycol 8000
`(Union Carbide Corporation) were stirred for one hour to
`fully hydrate the polyethylene glycol. The two solutions
`were mixed and stirred for an additional 0.5 hour. The
`
`solution was then top sprayed using a Niro MP-1 fluidized
`bed on 741.8 grams of ibuprofen powder. The inlet tem-
`perature was 69-73° C. and the outlet temperature 33-38° C.
`The velocity of the air passing through the fluidized bed
`ranged from 42-74 cubic meters per hour, and the tempera-
`ture of the ibuprofen ranged from 36—48° C. Spraying
`required a total of 2.5 hours. This Example 7A.
`By the same method as Example 7A, 600 grams of
`ibuprofen was coated with a combination of 250 grams of
`croscarmellose sodium, 20 grams of polyethylene glycol,
`and 435 grams of 30% ethylcellulose solution in 3322 grams
`of deionized water. The following ranges of conditions were
`recorded: inlet temperature 62-73° C., outlet temperature
`33—37° C., air velocity 41-79 cubic meters per hour, and the
`ibuprofen temperature 35—48° C. Spraying required about
`four hours. This is Example 7B.
`EXAMPLE 8
`
`By the method of Example 2, a dry blend comprising
`164.7 grams of ibuprofen coated with the slurry of croscar-
`niellose sodium, ethylcellulose, and polyethylene glycol
`(Example 7B), 79.0 grams of Avicel® PH-102, 592.4 grams
`of granular niannitol, 99 grams of Avicel® CE-15, 19.7
`grams of aspartame was tableted with sweeteners and fla-
`vorings to provide taste masked Ibuprofen tablets.
`EXAMPLE 9
`
`10
`By the same method, 600 grams of guiafenesin was
`coated with 250 grams of croscarmellose sodium, 20 grams
`of polyethylene glycol 8000, and 434 grams of a 30%
`ethylcellulose solution in 3322 grams of deionized water.
`The following ranges of conditions were recorded:
`inlet
`temperate 74—82° C., outlet temperature 35-41° C., tem-
`perature of the guiafenesin 37-52° C., and air flow velocity
`22-51 cubic meters per hour. Spraying required about 5.7
`hours. This is Example 9B.
`EXAMPLE 10
`
`By the method of Example 2, a dry blend comprised of
`164.7 grams of guiafenesin coated with the slurry of cros-
`carmellose sodium, ethylcellulose, and polyethylene glycol
`(Example 7B), 79.0 grams of Avicel® PH-102, 592.4 grams
`of granular mannitol, 99 grams of Avicel® CE-15, 19.7
`grams of Aspartame® was tableted with sweeteners and
`flavorings to provide a taste masked guiafenesin tablet.
`EXAMPLE 11
`
`In a large stainless steel Vessel was placed 124.3 Kg of
`purified water. The water was stirred with a propeller-type
`mixer, and 11.1 Kg of croscarmellose was added to the
`vortex of the stirred water. This mixture was stirred for 30
`
`in a second stainless steel con-
`minutes. Simultaneously,
`tainer was placed 11.7 Kg of a 30% ethylcellulose aqueous
`dispersion. This dispersion was stirred with a propeller