United States Patent 1191
`Augello et al.
`
`I lllll llllllll Ill lllll lllll lllll lllll lllll 111111111111111111111111111111111
`US006099865A
`[11] Patent Number:
`[45] Date of Patent:
`
`6,099,865
`Aug. 8, 2000
`
`[54) CROSCARMELLOSE TASTE MASKING
`
`FOREIGN PATENT DOCUMENTS
`
`(75]
`
`Inventors: Michael Augello, Marlboro, NJ.;
`Sheila M. Dell, New Hope, Pa.;
`George E. Reier, Somerset, N.J.;
`Howard J. Stamato, Bridgewater, NJ.;
`Lynn M. DiMemmo, Hamilton, N.J.
`
`(73] As.signee: FMC Corporation, Philadelphia, Pa.
`
`[21) Appl. No.: 09/330,445
`
`[22] Filed:
`
`Jun. 11, 1999
`
`Related U.S. Application Data
`(60]
`ProvL~ional application No. 60/091,996, Jul. 8, 1998.
`lnt. Cl.7
`(51)
`... ...................................... ..... ....... .. A61K 9/62
`[52) U.S. Cl. .......................... 424/494; 424/489; 424/464;
`424/495; 424/470
`[58) Field of Search ..................................... 424/489, 464,
`424/470, 468, 458
`
`[56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`6091150
`
`4/!994
`
`Jap• n.
`
`Primary Examiner-Thurman K. Page
`Assistant Examiner-William E. Benston
`Auomey, Agent, or Firm-FMC Corporation
`
`(57]
`
`ABSTRACT
`
`The present invention describes the use of croscarmellose
`sodium to coat bitter-tasting active agents in a manner that
`will mask lhe biller taste of these materials, taste masked
`pharmaceutical compositions [o which the particles of phar(cid:173)
`maceutically act ive agent are coated with croscarmellose
`sodiu m, tas te masked pharmaceutical tablets made
`therefrom, in which Lhe rapid disintegration of tablets that is
`imparted by croscarmellose sodium is preserved, and to a
`method for preparing such coated particles by preparing
`Lhem in a fiuidized bed coating process.
`
`5,874,4 18
`
`2/ 1999 Stella cl al. ............................... 514/58
`
`12 Claims, No Drawings
`
`DRL - EXHIBIT 1021
`DRL001
`
`

`
`6,099,865
`
`2
`Tbcse findings are particularly surprising aod unexpected in
`view of the fact that croscarmellose sodium has not herelo(cid:173)
`fore been used as a taste masking agent.
`
`BRIEF SUMMARY OF THE INVENTION
`Accordingly, in accordance witb a first aspect of this
`invention there is provided a particulale taste masked phar(cid:173)
`maceutical composition comprising a substrate which con(cid:173)
`sists essentially of particles of a pharmaceutically aclive
`10 ageo1 having ao objec1iooably bitter taste coated with a taste
`masldng amount of croscarmellose sodium, the amount of
`the coating being in the range of 10 10 SO percent by weight
`of the substrate.
`In accordance with a second aspect of this invention there
`is provided a method fo r masking 1be biller taste of a
`pharmaceutically active agent without separate coating and
`disintegram agents which comprises:
`(a) Auidiziog in fluidized bed coating apparatus a sub(cid:173)
`strate having a particle size in the range of 50 to 500
`microns consisting essentially of an objectionably bit(cid:173)
`ter tasting pharmaceutically active agent;
`(b) Spraying into said fluidized bed an aqueous solu1ion of
`croscarmellose sodium an amount in the range of 10 to
`SO percent by weight of said substrate; and
`(c) Recovering a taste masked coaled pharmaceutical
`composition consisting essentially of said pharmaceu(cid:173)
`tically ac1ive agent coated with a taste-masking amount
`of croscarmellose sodium.
`la yel anolher embodiment of the invention tbere is
`provided a taste masked pharmaceutical dosage form com(cid:173)
`prising a tablet for oral administration consisting essemially
`of a therapeutically effecLive amount of the particulate
`composition of 1he coated active ingredienl described above
`35 in admixture with one or more compatible pharmaceutically
`acceptable adjuvants, in wbicb croscarmellose sodium
`serves as both taste maskiog agent and dispersant, wi1hou1
`the need for additional dispersaots or coating agents or steps.
`
`1
`CROSCARMELLOSE TASTE MASKING
`
`Tbis application claims benefit of Provisional Applica(cid:173)
`tion Ser. No. 60/091,996 filed Jul 8, 1998.
`
`HbLl) OF TllE INVENTION
`
`5
`
`1ae present inven1ion rela1es 10 1be use of croscarmellose
`sodium lo coat biller-lasting active agenlS in a man ner 1ha1
`will mask 1be biller taste of 1bese maierials. More panicu(cid:173)
`larly the presenl invention relates 10 a panicula1e tasle
`masked pharmaceutical composition in wbicb par1icles of a
`pharrnaceu1ically active agenl are coated with croscarmel(cid:173)
`lose sodium. II also relates 10 taste masked pharmaceu1ical
`tablelS made therefrom, in which lbe rapid disintegralion of
`tablets that is imparted by croscarmellose sodium is pre- 15
`served. The invemion also provides a melhod for preparing
`the particulate 1aste masked pharmaceutical composiiions.
`
`BACKGROUND OF THE INVENTION
`
`20
`
`Croscarmellose sodium bas beeo widely used as a dis(cid:173)
`persan1 and disintegranl in the pharmaceutical industry. It is
`known to have been used as a '"super disiniegrant" for
`pharmaceutical tablelS where rapid disintegra1ion and/or
`dispersion is required 10 render pharmaceutical actives 25
`promptly physiologically available. Croscarmellose is typi(cid:173)
`cally used in such applications in combioatioo wi1b other
`pharmaceutically acceptable adjuvants such as binders,
`lubricanlS, dispersants, surface ac1ive agents and lbe like, all
`of which are well known to 1bose skilled in the an of 30
`formula ting pharmaceutically act.ive agenlS.
`Bitter tasting pharmaceutically active agents are par1icu(cid:173)
`larly dilliculi lo render palatable when placed in tableted
`dosage forms. Much resea rch and many techniques have
`been employed in the art 10 effectively mask the 1as1e of
`biller tas1ing pharmaceuticals wi1hou1 retarding the physi(cid:173)
`ological availability of lbe biller tasting ac1ive ingredients.
`Well known methods for taste masking generally bave
`involved coating of the particles of the active ingredient
`and/or tbe tablet containing such active ingredient, with 4o
`various coating materials or combinations of coating mate(cid:173)
`rials many or most of wbich have Limited waler solubility
`and are tberefore applied from organic media. However, on
`the one band, the more water soluble such coatings are, the
`less effective tbey are in 1as1e masking, aod oo the other band 45
`tbe less water soluble they are the more they tend 10 retard
`the physiological availability of the active ingredieol.
`Moreover, in order to achieve both rapid disinlegration and
`taste masking it has been necessary 10 use both a coating and
`a d isi ntcgrant or super disi n tcgrant, sucb as croscarmcllosc ~o
`sodium, io the tablet formulation. This is extremely costly io
`requiring both a coaling step and the addition of relatively
`costl y disintegrants. Accordingly there is a continuing need
`for less costly and more effect ive methods for achieving
`taste masking while at tbc same time assuring prompt 55
`physiological availability of the active ingredient. It is a
`further advantage of tbe present inveniion lbat the coating
`solution employed herein is entirely aqueous, so that there is
`oo organic residue left in the coated particles.
`It bas oow been found that these aod otber objects of Lbe 60
`invention can be achieved by utilizing croscarmellose
`sodium as botb a coating agent aod as a disintegraa1, thereby
`eliminating lbe need for use of separate coating and disin(cid:173)
`tegraots in labletiog formulations. 11 bas further been found
`that particle size of the active ingredient and the method 65
`used 10 coat the active both play an important role in lbe
`ability 10 use croscam1ellose sodium to serve both functions.
`
`DETAILED DESCRIPTION OF TI-IE
`INVEN"l10N
`lo accordance with tbe first aspect of this ioveoiioo, the
`particulate taste masked pharmaceutical composition com(cid:173)
`prises particles of a pharmaceutically active agent having ao
`objectionably bitter taste in which lbe par1icles of pharma(cid:173)
`ceutically active agent are coaled wiLh a taste masking
`amount of croscarmellose sodium. For purposes of this
`invention, in order to effecLively taste mask Lbe pharmaceu(cid:173)
`tical composition described above, it is generally necessary
`lo use s ligh tly more croscarmellose sodium for purposes of
`tas1e masking than is normally employed when employing
`croscarmellose sodium as a s11per disintegrant for pharma(cid:173)
`ceutical tableis. lo this invention, however, it is used to coat
`particles of the biller tasting pharmaceutical active ingredi(cid:173)
`ent ratbcr than as a simple additive or excipient wbicb is
`blended with the active agent or ingredient and 01ber adju(cid:173)
`vanlS in tbe tableting formulation . A5 a coaring material, ii
`is employed in an amou nt in 1be range of 10 to 50 percent,
`preferably in the range of 15 lo 28 percent, and most
`preferably from abou t 18 to about 2S percent by weight of
`the substrate to whicb it is applied as a taste masking
`coating. At these levels aod when applied as a coating as
`described below, it serves tbe dual function of acting as a
`taste masking agent aod as a super disin1egrant for tableted
`dosage forms.
`lo addition 10 lbe use of appropriate amounts of croscar(cid:173)
`mellose sodium as a coating for the active ingredient, the
`
`DRL - EXHIBIT 1021
`DRL002
`
`

`
`6,099,865
`
`10
`
`3
`particle size of tbe active ingredient is also important in
`achieving adequate taste masking. As shown in the examples
`below tbe taste masking efficacy of croscannellose sodium
`is dramatically reduced when the particle size of the sub(cid:173)
`strate is below about 60 microns and/or when a large
`p1.:n.:1,:ntagc of Lb1.: substrate bas a fi.ac partic.:10;: si:tc. Aocord(cid:173)
`ingly it is important to tbe preseat invention tha t the active
`ingredient which forms the substrate to be coated by tbe
`croscarmel.lose sodium bave a particle size in the range of 50
`to 500 microns, lbat not more than about 1 percent of lbe
`particles have a particle size smaller Lhan 60 microns and/or
`that not more Lhan aboUL 1.5 percent of the substrate particles
`have a particle size less than about 125 microns. Accord(cid:173)
`ingly it is preferred to use a substrate which is in crystalline
`form rather tha n in a powdered form. It is also important in 15
`the coating process to control the inlet temperature to
`maintain a temperature below the melting point of the
`substra te to be coated to that the substrate does not melt
`during tbe coating process.
`la order to increase adherence croscarmcllose to the 20
`active ingredient particles, a binder may be added to the
`coati ng solution or suspcosioo. Su itable binders include
`ethylcel lu lose, bydroxypropylmelbyl cellu lose,
`methylcellulose, polyviaylpyrrolidoae, or other binders con(cid:173)
`ventionally employed io pharmaceutical preparations. lo 25
`general these binders are used in lhe present invention at
`very low levels simply to assure that the croscarmellose
`coating strongly adheres to the particulate pbarmaceutical.ly
`active agent. Though these ranges may vary with the par(cid:173)
`ticular binder or formulation, they are suitably employed at 30
`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 tbe range of about 4 to
`about 6 percent by weight. These levels arc substantially 35
`below the level at which these binders are normally used for
`otbcr purposes in some pharmaceutical preparations, for
`example as coterie coatings or taste masking agents.
`Advantageously, plasticizers may also be included ia the
`coating solutions or suspensions of the present invention for 40
`the purpose of plasticizing the cthylccllulose sufficiently to
`provide it with sufficient flexibility and hardness to prevent
`the coating from being abraded or destroyed when tbe
`coated particles are subsequently handled in processing
`equipment and/or compressed into tableted dosage forms. 45
`Suitable plasticizers include polyethylene glycol having a
`molecular weight in lbe range of 200 up to about 8000,
`propylene g lycol, g lyceri n, g lycerin triaceta te,
`triethylciirate, dibutylsebacaie (DBS), or other conventional
`plasticizers for pharmaceutical preparations. T he amount of ~0
`plasticizer employed may vary over a wide range depending
`on ihe plasticizer used and the binder employed in ihe
`formulation, it is generally preferred to utilize sufficient
`plasticizer to provide from about 0.2 io 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 lbe
`solid. lo the Wurster coater, a spray nozzle is placed under 65
`the fluidized bed, providing a bottom spray which coats lbe
`fluidized particles. A preferred method of coating the par-
`
`4
`tides 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 maaufactmer of a top spray fluidized
`5 bed coater is tbe 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 J'luidized bed coaling opera-
`tions is that these are batch operations.
`Thus the preferred process aspect of lhis iaveotioa is a
`coating process in which a granular substrate is directly
`coated. Althougb wet granulation techniques bave been
`allempted in an effort to increase part icle size of the active
`ingredients with and without croscarroellose 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 proccs.sing steps rendering tbem less cost
`effective. Tims, 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 bas a bitter taste that
`requires taste masking. Examples of suitable substrates
`include acetaminophen, ibuprofen, ketoprofeo, other similar
`members of this class of ooasteroidal anti-iallammatory
`agents, guiafenesin, dext romeiborpbao, chloropbeoirimioe,
`and bromopheairimiae. The active ingredient may be highly
`water soluble or have limited water solubil ity. Those skilled
`in the art of taste masking will appreciate that numerous
`otber pharmaceutical actives which have a particularly
`objectionable biller taste may also be taste masked ia
`accordance with tbe present invention.
`It wiJl be appreciated by those skilled in the coating aod/or
`taste masking art tbai sorac experimentation may be required
`witb cacb 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 bas 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 tbc spirit and scope of
`this invention. This material passing througb an appropri(cid:173)
`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 eJieciive.
`When the coaled substrate is incorporated into the final
`iablet formulation, the amount of croscarmellose sodium in
`the iableied formula tion will generally be in the range of
`about 1-10% by weight of tbe fiaisbed tablets. Since this is
`ai or slightly above the range at which croscarmellose
`sodium is norma!Jy employed as a disiotegraot in tablets or
`tableting formulations its dual functionality as a coating and
`55 taste masking agent aod as a disin tcgraot for tablets formed
`from the coated composition of this invention w ill be readily
`apparent to those skilled in the formu lation and taste mask(cid:173)
`ing art.
`The product of the process is preferably a free Howing
`60 particulate granular material comprising the particulate
`pharmaceutically active agent having a coating comprising
`croscarmellose sodium, a binder, aod optionally a plasti(cid:173)
`cizer. Tbe product may be compressed as such into taste-
`masked tableted dosage forms, or may be blended with
`tableting additives coaveatioaaUy used in the formulation of
`pharmaceutical tablets then compressed into a tableted dos-
`age forms. Such additives include, for example, fillers such
`
`DRL - EXHIBIT 1021
`DRL003
`
`

`
`6,099,865
`
`6
`
`'JA.BLE 1
`
`Pan icle size
`
`Crystalline
`
`Exaniple
`
`5
`
`(n1icrons)
`
`>500
`297- 500
`210-297
`125-210
`62-125
`<62
`
`APAP
`
`0.53%
`66.44%
`32.59%
`0.44%
`0
`0
`
`lA
`
`l6
`
`IC
`
`9.1 7%
`87.13%
`2.68%
`0.46%
`0.56%
`0
`
`l0.21%
`86.96%
`J.31%
`0.19%
`0.28%
`l.05%
`
`3.57%
`73.90%
`9.13%
`3.77%
`4.07%
`5.56%
`
`EXAMPLE 2
`
`5
`as microcrystalline cellulose and/or various gums, sweetners
`such as Aspartame®, Prosweet®, mannitol, sucrose, or other
`swcetners, fl.ow aids such as magnesium stearate, and other
`additives conventionally employed in preparing tableting
`formulations.
`
`The following examples fuJther 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 10
`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 15
`sample and compared it with a control sample and reported
`whether on not in their opinion the tcsL sample effectively
`masked the biller taste of the active ingredient. The percent(cid:173)
`age number given in the example is thus a rellectio n of the
`percentage of tests in which the test sample was judged 20
`effectively taste masked.
`
`lo a large twin shell blender were placed 253.2 grams of
`acetaminophen crystals which had been sprayed with a
`slurry of croscarmellosc sodium (Example lA) and 189.9
`grams of Avicel® CE-15 (microcrystaJl ine ce!Julose/guar
`gum, 85/15, sold by FMC Corporation, Pbiladelpbia, 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 tbe blender, and mixing was
`continued for an additional 10 minutes. Next, 384.9 grams
`25 of granular mannitol was added lo tbe blender, follo\ved by
`10 more minutes of mixing. Finally, 7.6 grams of magne(cid:173)
`sium stearate wbich bad been passed through a 30 mesh US
`Standard screen was added and blended for 3 minutes. This
`composition was compressed on a B2tablet press operated at
`39 RPM and fitted with round, 9.525 mm (0.375 inch)
`diameter, standard convex tooling. The upper compression
`fo rce was in the range of 900 to 1100 Kg and the lower
`compression fo rce averaged WOO Kg. The average weight,
`thickness, a.ad 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(cid:173)
`utes. Taste masking was approximately 95%. This is
`Example 2A. Two additional identical formu lations,
`Examples 2B and 2C, were prepared, respectively, from
`ace taminophen coated with croscarmeUose sodium io
`Examples 1B and lC. 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 e ither Formulation 2/\. and
`exhibited minor bitterness of the acetaminophen. The tablet
`properties of these tablets are shown in Table 2.
`
`30
`
`Example 1 describes the preferred method of coating
`crystalline acetaminophen witb a croscarmellose solution
`using a top spray and a fluidized bed. Example 2 shows the
`preparation of tablets and results of tbe taste masking
`produced by the coatings of Example l 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(cid:173)
`coated acetaminophen. Example 4 is indicative of the lower
`limit of croscarmellose scxlium which must be used to 35
`provide effective taste masking. Example 5 is a comparative
`example to show the effect of no coating at all. Example 6
`uses tbe same commercial, solvent-coated, crystalline
`acetaminophen that was used in Example 3, and is i.ncluded
`to sbow tbe greatly reduced friability of using croscarmel-
`lose sodium-coated acetamioopben in a rapid tablet press as
`compared witb tbe current commercial material. Examples 7
`and following demonstrate the coating process of tbe present
`invention witb ibuprofen, guiafenesin and acetaminophen 45
`utilizing a binder and plasticizer in the coating solution.
`
`40
`
`EXAMPLE 1
`
`lo a fluidized bed coater with a bowl insert was placed LO ~o
`Kg of crystalline acetaminopben. A slurry of 250 grams of
`croscarme!Jose 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 tbe coating process the
`inlet temperature and tbe outlet temperature were main(cid:173)
`tained at 80° C. and 36° C., respectively. Tbe percentages of
`particles of various sizes were de termined by passing the
`product througb a stack of sieves, each one finer than the one
`above it. This is Example lA for which the particle size
`distribution is sbowo in Table 1. Two addit.iooal identical
`coatings were made except that double tbe amount of each
`ma terial was used. These are Examples 1.B and lC. Sieve
`analysis data for eacb of tbcse materials are sbown in Table 65
`I also. A comparative sieve analysis of the substrate crys(cid:173)
`talline acetaminophen is also included in Table l.
`
`60
`
`55
`
`'JA.BLE 2
`
`Example
`
`2B
`
`0.384
`4.37
`5.94
`
`2J\
`
`0.413
`5.56
`7.64
`
`2C
`
`0.3721
`4.33
`4.37
`
`Tablet Property
`
`Weighl (gram)
`Thickness (mm)
`Hardness (Kp)
`Conipression force
`
`Upper (Kg)
`Lowe r (Kg)
`Disintegration (min)
`Friabitity (%)
`
`900-1100
`1000
`-2
`0.0239%
`
`NR'
`NR
`<1
`0.1 25%
`
`' R
`' R
`<1
`0.252%
`
`' NR- not recorded
`
`EXAMPLE 3
`Using Lbe procedure of Example 2, 25.27 grams of
`acetaminophen powder which bad been coated wi th a slurry
`
`DRL - EXHIBIT 1021
`DRL004
`
`

`
`6,099,865
`
`8
`
`"JABLE4
`
`Example
`
`Tablet Property
`
`3 A
`
`36
`
`3C
`
`Weight (gram)
`T hickness (mm)
`Hardness ( Kp)
`Disintegratio n (min)
`Friabiiity (%)
`
`0.3496
`4.44
`3.44
`<0.5
`l .O
`
`0.361 4
`4.45
`4.67
`<0.5
`0.83
`
`0.416
`4.62
`9.1
`<3
`0.65
`
`7
`of croscarmellose sodium in a Wurster fluidized bed using a
`bottom spray was placed in a twin shell blender. The weight
`ratio of acetaminopben powder to croscarmellose sodium
`was 85:15. Then, 16.13 grams of Avicel® CE- 15
`(cnicrocrystalline ce tlulose/guar gum, 85/15, sold by FMC 5
`Corporation, Pbiladelpbia, Pa. 19103) was added to lbe
`blender and blended for 10 minu tes. At lhe end of Lbis
`period, 5.10 gr ams of Avicel Pll-102, 4.84 grams of Aspar(cid:173)
`tame® powder, 0.54 gram of Enhance® and l.07 grams of 1o
`ProSweet® were added to tbe blender, and mixing was
`continued for an additional 10 minutes. Nexl, 46.24 grams
`or granular mannilol was added io blender, followed by 10
`mo re minutes of mixing. Finally, 0.8 gram of magnesium
`stearate wbicb had been passed Lhrough a 30 mesh US 15
`S tandard screen was added and blended for 3 minutes. TI1is
`composition was compressed on an F tablet press fitted with
`round, 9.525 mm (0.375 incb) diameter, standard convex
`tooling. Tbe average weight, thickness, and ha rdness of 20
`these tablets were, respectively, 0.3496 gram, 4.44 mm
`(0.1749 ioch), and 3.44 Kp. Friability after 4 minutes was
`1.0%, and tablet disintegration Lime in 37° C. water wit bout
`stirring was less lban 30 seconds. Taste masking was
`approximately 85%. Tbis is Example 3A.
`
`EXAMPLE4
`In a large twin shell blender were placed 228.5 grams of
`acelaminopben powder which had been coated witb a slurry
`of croscarmellose sodium in a Wurster fluidized bed appa(cid:173)
`ratus using a bollom spray. The ratio of acetaminop ben 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,
`Ph iladelpbia, Pa. 19103), 32.2 grams of Aspartame®
`powder, 26.9 grams of ProSwect®, 21.5 grams of fruit
`puncb flavor, and 2.69 grams of anhydrous citric acid. These
`25 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
`30 through a 30 mesb US Standard screen was added and
`blended for 5 minutes. This composition was compressed on
`a 512 tablet press filled with round, 9.525 mm (0.375 inch)
`diameter, standard convex tooling. There was very slight
`taste masking exhibited by these tablets.
`
`35
`
`EXAMPLES
`
`A portion of the coated acetaminophen powder used to
`prepare Example 3A was passed through a 100 mesh U.S.
`S tandard 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 lo 90%
`by using only the larger coated particles.
`
`A comparative formulation was prepared in which com(cid:173)
`mercia I coated, crystalli nc ace taminophe n (Eu ra ad
`America) replaced tbe croscarmellose-coated acetami(cid:173)
`nophen. The Eurand material is a solvent-coated material, 40
`makiog slight adjustments neces.5ary in the weights of other
`components 10 provide the same amount of acetamioophen
`per tablet. This comparative formula tion is Example 3C
`which provided 95% taste maskiog of the acetaminophen.
`The formulations of Examples 3A, 3B, and 3C are shown in 45
`Table 3, and the corresponding tablet properties are shown
`in Table 4.
`
`In a twin sbell blender were placed 64.35 grams of
`acetaminophen crystals and 60.33 grams of Avicel® CE-15
`(microcryslalline cellulose/guar gum, 85/ 15, sold by FMC
`Corporation, Philadelphia, Pa. 19103). These components
`were blended for 10 mioutes. At Lhe end of ibis period, 36.48
`grams of Avicel PH-102, 6.04 g rams of Aspartame®
`powder, and 6.04 grams of ProSweet® were added to lhe
`blender, and mixing was continued for an additional 10
`minu tes. Next, 120.83 grams of granular maonitol was
`added to blender, followed by 10 more minutes of mixing.
`Finally, 2.4 grams of magnesium stearate which bad been
`passed th rough a 30 mesh US S tandard screen was added
`and blended for 3 mioutes. This composition was com-
`~o pressed oa a B2 tablet press operated at 39 RPM aad fi tted
`witb round, 9.525 mm (0.375 inch) diameter, standard
`convex tooling. The upper compression force averaged
`1900.5 Kg. Tbe average lbicknes.5 and hardness of lhesc
`tablets were, respectively, 4.32 mm (0.1699 inch), and 5.38
`ss Kp. Tablet disintegration time in 37° C. water without
`stirring was less than l minute. There was no taste masking,
`and tbe tablets were described as baving a bitter, metallic
`taste wi th a long-lasting aftertaste.
`
`60
`
`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
`(roicrocryslalline cellulose/guar gum, 85/15, sold by FMC
`65 Corporation, Philadelphia, Pa. 19103). These componems
`were blended for 10 minutes. At the end of this period, 113.9
`grams of Avicel PH-102, 25.3 grams of Aspartame®
`
`TABLE 3
`
`Formulatio n
`Components
`
`Coated Al'AP
`Aviccl P H-102
`Maonitol•
`Aviccl CE-15
`Aspartame
`Pro Sweet
`Enhance
`Mgstcamte
`
`3A
`(grams)
`
`25.27'
`5.JO
`46.24
`16.13
`4.84
`1.07
`0.54
`0.82
`
`Example
`
`313
`(grams)
`
`'25.21'
`5.10
`46.24
`J6.J 3
`4.84
`1.07
`0.54
`0.82
`
`JC
`(grams)
`
`24.'25°
`5.18
`46.87
`16.35
`4.90
`1.09
`0.54
`0.82
`
`'Croscarmellosc sodium-coated acetaminophen powder comprising par(cid:173)
`ticles larger and smaller than 149 microns
`ueroscarmellose sodium-~-ooted acetaminophen powder in w hich all par(cid:173)
`ticles were larger t ban 149 microns
`•coated acetaminophen (Eura nd America}
`"Omnular mannitol
`
`DRL - EXHIBIT 1021
`DRL005
`
`

`
`6,099,865
`
`9
`powder, and 25.3 grams of ProSweet® were added to tbe
`blender, and mixing was continued for an additional 10
`mioutes. Next, 384.8 grams of granular manoitol was added
`to bleoder, followed by 10 more minutes of mixing. Fioally,
`7.6 grams o[ magnesium stearate wbicb bad been pas.sed s
`through a 30 mesh US S tandard screen was added and
`blended for 3 minutes. This composition was compressed on
`a B2 tablet press operated at 39 RPM and fi tted with round,
`9.525 mm (0.375 inch) diameter, standard convex tooling.
`The average weight, thickness, and hardness of these tablets 10
`were, respectively, 0.3921 gram, 4.39 mm (0.173 iacb), and
`6.53 Kp. The friabili ty of these tablets was 2.84%, and the
`disimegratioo rime in 37° C. water without stirring was less
`than 1 minute. An upper compression force or at least 1500
`Kg was required to provide tablets having the properties J S
`described above. There was, however, approximately 95%
`taste masking of the bitter taste of acetaminophen.
`
`10
`By the same method, 600 grams of guiafenesin was
`coated with 250 grams of croscarmellosc sodium, 20 grams
`of polyethylene glycol 8000, and 434 grams of a 30%
`etb ylcel1ulose solution in 3322 grams of deionized water.
`The following ranges of conditions were recorded: inlet
`lc.:mpc.:ralc.: 74-82" C., outlet Lc.:mpcraturc.: 35-41" C., tc.:m(cid:173)
`perature of the guiafenesin 37-52° C., and air flow velocity
`22-51 cubic meters per hour. Spraying required about 5.7
`bours. This is Example 9B.
`EXAMPLE 10
`By the metbod of Example 2, a dry blend comprised of
`164.7 grams of gu iafcnesin coated with tbe slurry of cros(cid:173)
`carmellose sodium, ethylcellulose, and polyethylene glycol
`(Example 7B), 79.0 grams ofAvice l® PH-102, 592.4 grams
`of granular maooitol, 99 grams of Avicel® CE-15, 19.7
`grams of Aspartame® was tableted with sweeteners and
`llavorings to provide a taste masked guiafenesin tablet.
`
`EXAMPLE 7
`A large beaker was charged with 2464.5 grams of deioo- 20
`ized water which was stirred w ith a propeller stirrer. To this
`water was added L85.5 grams of croscarmellose sodium.
`Mixing was continued for one hour to folly hydrate the
`croscarmellose sodium. lo a second container, 193 grams of
`30% etbylcellulose 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 g lycol. The two solutions
`were mixed and stirred for an additional 0.5 hour. The
`solution was then top sprayed using a Niro MP-1 lluidized
`bed on 741.8 grams of ibuprofen powder. The inlet tem(cid:173)
`perature was 69-73° C. and the outlet temperature 33-38° C.
`The velocity of the air passiog through the fluidized bed
`ranged from 42-74 cubic meters per hour, and the tempera(cid:173)
`ture of the ibuprofen raoged from 36-48° C. Spraying 35
`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. Tbe following ranges of conditions were
`recorded: inlet temperature 62- 73° C., outlet temperature
`33-37° C.