`
`United Stat�s Patent
`4,916,161
`c191
`[11]Patent Number:
`[45]Date of Patent:
`Apr. 10, 1990
`Patell
`
`[56]
`
`[54]TASTE-MASKING PHARMACEUTICAL
`References Cited
`
`AGENTS
`U.S. PATENT DOCUMENTS
`
`
`
`
`
`4,460,563 7/1984 Calanchi ............................. 424/494
`
`[75]Inventor:
`
`Mahesh K. Paten, Edison, N.J.
`[73]Assignee:
`
`Bristol-Myers Squibb, New York,
`Kight
`Primary Examiner-John
`N.Y.
`M. Nutter
`
`Assistant Examiner-Nathan
`[21]Appl. No.: 262,911
`
`
`M. Nolan Attorney, Agent, or Finn-Sandra
`[22]Filed:Oc t. 25, 1988
`ABSTRACT
`[57]
`[51]Int. Cl.4 ......................... A61K 9/62; BOlJ 13/02;
`
`The unpleasant taste of ibuprofen or other bad-tasting
`
`
`BOSO 7/00; B22B 9/02
`
`
`pharmaceuticals can be mediated via wet granulation
`
`[52]U.S. Cl ..................................... 514/570; 514/781;
`
`
`
`using certain taste masking agents.
`
`514/974; 427/3
`
`[58]Field of Search ....................... 514/570, 781, 974;
`
`427/3
`13 Claims, No Drawings
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2041 - 1/4
`
`

`

`1
`
`4,916,161
`
`TASTE-MASKING PHARMACEUTICAL AGENTS
`
`This invention relates to a process for taste masking
`ibuprofen or other unpleasant tasting substances. More
`particularly, it concerns a process for wet granulating a
`mixture of ibuprofen, and hydroxypropyl methylcellu-
`lose phthalate (hereinafter sometimes referred to as
`' HPMCP) with an aqueous composition in which the
`HPMCP is at least partly soluble to affect an improve-
`ment in the taste of ibuprofen.
`The unpleasant taste of ibuprofen is well documented
`in the prior art and the efforts to overcome this bad taste
`have been numerous. One such effort involves convert-
`ing the ibuprofen to an aluminum salt and US. Pat. No.
`4,361,580 is exemplary of such efforts.
`Other suggested procedures for masking the taste of
`ibuprofen involve the preparation of derivatives of ibu-
`profen that» do not have its unpleasant taste. US. Pat.
`No. 4,049,700 prepares ibuprofen p-hydroxyphenylurea
`ester while US. Pat. No. 4,049,699 provides ibuprofen
`p-hydroxybenzaldehyde semicarbazone ester for the
`same purpose.
`’
`Still other procedures taught in the prior art suggest
`coating finished tablets of ibuprofen with taste-masking
`water insoluble ethylcellulose. US. Pat. No. 4,693,896
`is an example of this kind of procedure. Another
`method is disclosed in Japanese Patent No. 81/46,837
`which suggests coating particles of ibuprofen with ,8-
`cyclodextrin (i.e., beta-cyclodextrin). See Chemical
`Abstracts Vol. 95, (1981) page 382, 95:156580m. How-
`ever, B-Cyclodextrin is not approved for internal use in
`the United States. It is only allowed for internal use in
`Japan and Eastern European countries. Also, B-
`cyclodextrin is very expensive and is known to interfere
`with, and modify, the bioavailability of drugs due to its
`property to form complex with the drug molecule.
`Hydroxypropylmethyl cellulose phthalate has been
`widely used in the United States, in Japan and in Euro-
`pean countries as an enteric coating polymer. It is listed
`in the National Formulary (NF) making it an official
`compendium material. It is relatively inexpensive com-
`pared with B-cyclodextrin, commercially available and
`widely used in the food and pharmaceutical industries.
`It has now been found that a highly satisfactory ibu-
`profen product, in which the bad taste of the ibuprofen
`is effectively masked, can be made by wet granulating
`the combination of ibuprofen and HPMCP with an
`aqueous granulating composition in which the HPMCP
`is at least partially soluble. Since the HPMCP is not
`soluble in pure water, it is necessary to adjust the pH of
`the aqueous granulating composition with an alkalizing
`agent or a buffering system so that it has a pH of 5.5 or
`higher. The ibuprofen granulations prepared in this
`fashion may be used as such, or they may be compressed
`into tablets, as described in more detail below.
`The concepts of wet granulating and the granulations
`prepared by such a process are well known to those
`skilled in the pharmaceutical arts. In a wet granulating
`process, the material to be granulated, usually in pow-
`dered form, it wetted with an aqueous composition of a
`granulating agent to cause the powdered material to
`agglomerate. This agglomerated product
`is
`subse-
`quently dried and then generally ground to reduce the
`size of the agglomerates to a size that is suitable for use.
`Usually, this type of process is used to form tablets of
`the material.
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`45
`
`50
`
`55
`
`60
`
`65
`
`2
`The granulation particles prepared by such a process
`are quite distinct from granules obtained merely by
`grinding larger pieces of a material to reduce its particle
`size. For instance, the granulations prepared by this
`process are devoid of the unpleasant taste of ibuprofen,
`probably due to the coating of Hydroxypropyl methyl-
`cellulose phthalate which becomes partially soluble in
`presence of alkaling agents.
`The HPMCP used as the taste masking agent in the
`present invention is derived from hydroxypropyl meth-
`ylcellulose by esterification with phthalic anhydride.
`HPMCP is sold commercially by Shin-Etsu Chemical
`and is described in detail in its publication entitled “Hy-
`droxypropyl Methylcellulose Phthalate, Technical Bul-
`letin of HPMCP Appendix-2” Biddle Sawyer Corpora-
`tion, New York, N.Y., which publication is incorpo-
`rated herein by reference.
`As is clear from this publication, the HPMCP is avail-
`able in at least two grades, i.e. HP—50 and HP—55, which
`differ a little from each other in the analysis of the sub-
`stituent groups on the cellulose backbone,
`i.e. free
`phthalic acid, carboxybenzoil groups, methoxy groups
`and hydroxypropyl group. Either of these grades of
`HPMCP may be used in the practice of this invention.
`HPMCP is also available commercially under the trade-
`mark SD EUDRAGIT L100.
`In making the granulations of the present invention, it
`has been found to be effective to first prepare a dry
`pregranulation blend containing the ibuprofen and
`HPMCP. The granulating solution is then added to this
`pre-granulation blend to form the granulation which is
`further processed to obtain the granulation in suitable
`form and size for use as such as a dosage form or as one
`component of a composite dosage form. The quantity of
`ibuprofen that may be contained in said pre-granulation
`blend may vary somewhat. However, generally it will
`comprise from about 10% to about 50% by weight of
`said pregranulation blend based on the total weight of
`said blend and preferably from about 30% to about 40%
`by weight on the same weight basis.
`Similarly, the quantity of HPMCP that may be con-
`tained in, the pre-granulation blend may also vary some-
`what. In the usual cases the HPMCP will constitute
`from about 5% to about 15% by weight of the pre-
`granulation blend based on the total weight of the pre-
`granulation blend. In the preferred cases, the HPMCP
`will comprise about 8% to about 10% of the pre-granu-
`lation blend on the same weight basis.
`In addition to the ibuprofen and HPMCP, the pre-
`granulation blend may also contain a variety of adju-
`vants commonly added to pre-granulation blends of this
`character. Thus, suitable quantities of such agents as
`sugars, Dextrose, Sorbitol and mannitol; bulking agents,
`such as Microcrystalline Cellulose, and starch and the
`like can be used Other conventional excipients can be
`employed.
`.
`The granulating composition used in this invention is
`an aqueous composition in which the HPMCP is at least
`partially soluble. HPMCP is insoluble in pure water and
`consequently pure water is not suitable as a granulating
`composition. HPMCP, however, is soluble in aqueous
`alkaline solutions or solutions that are buffered at a pH
`of about 5, preferably about 5.5 or greater. Aqueous
`acid solutions, even though they have a pH of about 5
`will not adequately dissolve HPMCP and consequently
`cannot bee employed as granulating solution.
`In general terms, it may be said that the granulating
`compositions that may be utilized in the present inven-
`
`»
`
`Mylan v. Qualicaps, |PR2017-00203
`QUALICAPS EX. 2041 - 2/4
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2041 - 2/4
`
`

`

`4,916,161
`
`4
`are known in this art that may be used for the present
`purposes. These include stablizers, colorants, fillers, and
`the like. Useful materials include fillers such as direct
`compressible sugars, Dextrose, Sorbitol, or Mannitol;
`compression aids e.g., microcrystalline cellulose, starch;
`lubricants, such as stearates; stearic acid, variety of
`flavors and flavor enhancers such as prosweet, magnas-
`weet, citric acid.
`The ratio of the amount of ibuprofen granulation
`product described above to the total amount of tablet
`adjuvants employed in making the present tablets may
`vary somewhat. Generally, on a weight basis (based on
`the tablet composition weight), from about 1 parts to
`about 3 parts of total tablet adjuvants will be mixed with
`about
`1 part of ibuprofen granulation, with the pre-
`ferred range being from about 2 parts to about 3 parts of
`total adjuvants to about 1 part of ibuprofen granulation
`product.
`The final blend of ibuprofen granulation product and
`tablet adjuvants is fed to tablet presses in which the final
`tablets are formed. This is a standard procedure and is
`well known to those skilled in this art and need not be
`elaborated on here.
`
`While the discussion herein centers on ibuprofen, it is
`contemplated that other foul-tasting pharmaceutical
`agents, e g. quaifenesin, acetaminophen; caffeine, and
`the like, can also be taste-masked using the invention.
`The following Examples are given to further illus-
`trate this invention. It is to be understood, however,
`that this invention is not limited thereto.
`
`EXAMPLE 1
`
`
`Formula 2584
`
`mg/
`Item
`
`tablet
`No.
`Ingredients
`% w/wt.
`
`3
`tion are aqueous compositions selected from the group
`consisting of aqueous alkaline solutions and aqueous
`solutions containing one or more buffering systems that
`buffer the pH of the aqueous solution at a pH of 5 or
`greater. The upper pH range of the granulating compo-
`sition used in the present invention does not appear to
`be a critical feature. However, as a practical matter, it
`generally will not exceed a pH of about 8.0.
`Types of granulating compositions that has been
`found to be particularly advantageous in the practice of
`the present invention are buffered aqueous composi-
`tions prepared by dissolving an alkali metal citrate, e.g.
`potassium citrate, in an aqueous carrier. In this case, the
`concentration of the alkali metal citrate in this aqueous
`composition will generally be in the range of from about
`50% to about 80% by weight, preferably about 60% to
`about 70%, based on the total weight of the aqueous
`granulating composition. This will generally give a pH
`in the range of from about 4 to about 7 and preferably in
`the range of from about 5 to about 6.
`In addition to the alkalizing agent or buffering system
`the aqueous granulating composition used herein may
`also contain other a'djuvants. These include flavoring
`agents, binding agents, processing and the like. Exam-
`ples of such adjuvants include sweetners such as saccha-
`rin, aspartame; flavoring agents such as artifical and or
`natural flavors, citric and tartaric acids. Binders such as
`starch, povidone; flavor enhancers, such as magnasweet
`and prosweet. The quantities used are suitable for their
`function in the compositions.
`In practicing the process of the present invention, a
`dry pre-granulation blend will be prepared by dry-
`blending and thoroughly mixing the desired quantity of
`ibuprofen, HPMCP and the desired adjuvants. The
`aqueous granulating composition described above is
`then added to the pre-granulation blend and the two are
`mixed until a uniform granulation is obtained. The rela-
`tive quantities of pre—granulation blend and aqueous
`granulating composition that will be mixed together
`may vary. Generally, on a weight basis from about 0.05
`parts to about 0.2 parts of aqueous granulating composi-
`tion will be used per part of pre-granulation blend. For
`optimum results, this ratio is from about 0.09 parts to
`about 0.1 parts of aqueous granulating composition per
`part of pre‘granulation blend.
`The granulation mass prepared as described above is
`ground in any suitable manner and then dried. Any of a
`number of devices and techniques known in this art can
`be used to perform these steps. Thus, a Tornado Mill or
`similar device may be used to grind the granulation. A
`fluid bed dryer may be used to dry the ground granula-
`tion. Other conventional processing apparatuses and/or
`techniques may be employed.
`The dried granulation product is then sized using any
`of several well known techniques. One very suitable
`procedure involves the use of an oscillating screen,
`having mesh size in the range of from 12 mesh to about
`16 mesh. Similarly, sizing of the particles can be also
`achieved by using Tornado Mill, Fitz Mill, or quick
`sieve machines, and the like.
`It is a feature of the present invention to use the gran-
`ulation described above to prepare ibuprofen tablets in
`which the bad taste of the ibuprofen is masked. To this
`end, this granulation is blended with tablet adjuvants
`that are added to facilitate the manufacture of the tablet,
`to improve its esthetics or to improve the organoleptics
`of the tablet or to serve as bulking agents for the tablet.
`Suitable quantities of a large number of tablet adjuvants
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`1
`2
`
`3
`
`4
`5
`6
`7
`
`8
`9
`
`10
`11
`
`12
`13
`14
`15
`
`9.346
`2.243
`
`5.607
`
`7.477
`
`0.374
`1.495
`
`7.663
`56.075
`
`1.121
`1.795
`
`0.561
`0.935
`0.075
`3.738
`
`50.00
`12.00
`
`30.00
`
`40.00
`
`2.00
`8.00
`
`41.00
`300.00
`
`6.00
`9.60
`
`Step B:
`
`Step C:
`
`Won—
`Ibuprofen USP
`Hydroxypropyl Methycellulose
`Phthalate
`PIP-55F (Shin-Etsu
`Chemicals) NF
`Cellulose Microcrystalline PH105
`NF
`Confectionery Sugar 6X NF
`Water, Deionized and Distilled
`Calcium Saccharin USP
`Potassium citrate USP
`M
`Mannitol Granular USP
`Sugar Compressible (DiPac-
`Amstlr) NF
`Calcium Saccbarin USP
`Citric Acid Anhydrous Powder
`USP
`Fruit Punch Flavor (FMC)
`3.00
`Magmsweet 180 Flavor Enhancer
`5.00
`FD a C Red #40 Lake - 15% Dye
`0.40
`Cellulose Microcrystalline PH101
`20.00
`NP
`
`1.495
`Magnesium Stearate USP
`16
`8.00
`100.000
`535.12!)
`—-——--———————__.._...____________
`PROCEDURE
`MM.
`Step A: Mix items 1, 2, 3 a 4 in Hobart mixer, mix for short 5
`minutes (screen each item separately if lumpy).
`Dissolve items 6 and 7 in 5 (use 500 ml water per 5680
`gm granulation), add to the product of Step A,
`complete granulation by adding 300 ml water.
`Mix until uniform granulation is formed.
`Pass the product of Step B through Tornado Mill.
`dry in fluid bed dryer, inlet temp. 60' C., outlet temp.
`30’ C. (approx. 1.5% LCD).
`
`Mylan v. Qualicaps, |PR2017-00203
`QUALICAPS EX. 2041 - 3/4
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2041 - 3/4
`
`

`

`4,916,161
`
` 5
`
`S“? D‘
`
`Step A:
`Step B:
`
`Step G:
`
`
`continued
`Formula 2584
`.
`~
`:figdggiufizfm’mn 0‘ Step C “mush #16 “5“”
`Pm n: DE! Mix and Find Blend
`Pass 10, 11, 12, 13, 14 and 15 through 30 mesh screen.
`Add mixture from Step A to small Twin Shell Blender
`)vith intensifier ber- Mix for 15 {ninutes “sips
`m: b“ 3 “‘3’ 2 “Vd‘mm‘s “eh “m “d
`Add to appropriate Twin Shell Blender Part1
`granulation, the product of Step B, item 8 (previously
`minutes.
`screened through #16 mesh screen) and item 9. Mix 15
`Step D: Add item 16 (previously screened through #30 screen)
`to mix of Step c for 5 minutes.
`Step E:
`Compress in tablet press to the following
`
`spec‘ficamm‘
`Punch a Shag
`13/?2" FFB
`M
`$3225]; 535 mg i 10%
`Moos"
`Hume“
`m
`Friability
`Less than 1%
`
`5
`
`15
`
`20
`
`25
`
`30
`
`6
`tgarlaiflation and the blend so formed is pressed mto
`4. The
`rocess according to claim 3, wherein the
`.
`P
`.
`.
`.
`weight who of total tablet adjuvants 1s m the range of
`from about 2 parts to 3 parts to about 1 part of ibuprofen
`grandam“-
`.
`_
`.
`5. The process according to clalm 3, wherem the pH
`of said aqueous granulating composition is adjusted
`with an alkalizing agent or a buffering system so that it
`1° has 3 PH 0f about 5-5 0{ 111811611 .
`‘
`.
`_
`6. The process according to claim 5, wherein said pH
`.
`.
`.
`.
`is adjusted with an alkali metal citrate.
`7. The process accordmg to claim 5, wherein said pH
`is adjusted in the range of from about 5.5 to about 8.
`8. The process according to claim 7, wherein said pH
`is adjusted with an alkali metal citrate.
`9. The process according to claim 8, wherein
`(a) said ibuprofen comprises from about 30% to about
`40% by weight of said pre-granulation blend based
`on the total weight of said pre-granulation blend;
`(b) said hydroxypropyl methylcellulose phthalate
`comprises from about 8% to about 10% by weight
`of said pre-granulation blend based on the total
`weight of said pre-granulation blend; and
`(c) said alkali metal citrate is present in said aqueous
`granulation composition at a concentration in the
`range 0f from about 60% to 3190‘“ 70% by weight
`Pascd on th? 30ml “might 0f said aqueous 81711111139
`111% COHlPOSltloni
`10. A process for preparing tablets containing a foul
`“Sting Pmacel}tical agent» in Whic}? fhe bad “Ste 0f
`the agent 15 effectively maSkedr compnsmg the Steps 0f:
`(3) Preparing an aqueous 5011113011 0f bUfferinS agent
`and sweetener;
`('3) Preparing a dry blend 0f the Phat!““mafia1
`agent, a taste-masking agent and non-active adju-
`vantsr admiXing and granulating the product of step
`(a) therewith;
`(C) milling and drying the product of step (b);
`(d) tableting the mixture.
`11. The process of claim 10 wherein the pharmaceuti-
`cal agent is ibuprofen and the taste-masking agent is
`hydroxypropyl methylcellulose phthalate.
`12. The process of claim 11 wherein the buffering
`agent is an alkali metal citrate.
`13. The process of claim 12 wherein the buffering
`agent is potassium citrate.
`*
`‘
`
`Reasonable variations, such as those which would
`occur to a skilled artisan, can be made herein without
`departing from the scope of the invention.
`what is claimed is;
`l. A process for preparing tablets containing a foul
`tasting pharmaceutical agent in which the bad taste of
`the agent is effectively masked comprising the steps of:
`(a) wet-granulating a dry particulate pre-granulation 35
`blend comprising the agent and hydroxypropyl
`methylcellulose phthalate with an aqueous granu.
`lating composition in which said hydroxypropyl
`methylcellulose phthalate is at least partially solu-
`ble to form: a granulation containing the agent;
`(b) grinding and drying the product of step (a);
`(c) blending the product of step (b) with tablet adju-
`vants; and
`(d) compressing the product of step (c) to produce
`tablets.
`2. The process of claim 1 wherein the agent is ibu—
`profen.
`3. The process according to claim 2, wherein tablet
`adjuvants are blended with said ibuprofen containing
`
`40
`
`45
`
`50
`
`"'
`
`*
`
`*
`
`55
`
`60
`
`65
`
`Mylan v. Qualicaps, |PR2017-00203
`QUALICAPS EX. 2041 - 4/4
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2041 - 4/4
`
`