United States Patent [19]
`Ratnaraj et al.
`
`I II llllll Ill lllll lllll lllll lllll lllll 111111111111111111111111111111111
`US005658919A
`5,658,919
`[11] Patent Number:
`Aug. 19, 1997
`[45] Date of Patent:
`
`[54] AQUEOUS PHARMACEUTICAL
`SUSPENSION AND PROCESS FOR
`PREPARATION THEREOF
`
`[75]
`
`Inventors: Sheila M. Ratnaraj. North Wales;
`Warren L. Sunshine, Dresher. both of
`Pa.
`
`5/1992 Beaurline et al. . ..................... 424/490
`5,112,604
`5,167,964 12/1992 Muhammad et al ................... 424/482
`5,173,305 12/1992 Grimberg ................................ 424/682
`5,196,436
`3/1993 Smith ...................................... 514/289
`5,272,137 12/1993 Blase ......................................... 514/54
`111994 Unger .......................................... 424/4
`5,281,408
`5,374,659 12/1994 Gowan, Jr ............................... 514/557
`5,409,907
`4/1995 Blase et al ................................ 514/54
`
`[73] Assignee: McNeil-PPC, Inc.. Skillman. N.J.
`
`FOREIGN PATENT DOCUMENTS
`
`[21] Appl. No.: 711,140
`Sep. 9, 1996
`
`[22] Filed:
`
`[63]
`
`[51]
`
`[52]
`
`[58]
`
`[56]
`
`Related U.S. Application Data
`
`Continuation of Ser. No. 383,542, Feb. 3, 1995, abandoned,
`which is a continuation of Ser. No. 48,701, Apr. 16, 1993,
`abandoned.
`Int. CI.6
`........................ A61K 31/505; A61K 31/44;
`A61K 31/445; A61K 31/135
`U.S. CI . .......................... 514/269; 514/289; 514/317;
`514/322; 514/357; 514/648; 514/653; 514/937
`Field. of Search ..................................... 514/269. 289.
`514/317. 322. 357. 648. 653. 937
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`3,539,365
`4,145,440
`4,327,076
`4,361,580
`4,427,681
`4,711,774
`4,716,033
`4,717,565
`4,761,274
`4,766,216
`4,772,724
`4,788,220
`4,822,876
`4,857,324
`4,882,324
`4,886,669
`4,895,723
`4,923,981
`4,975,465
`4,996,222
`5,013,557
`5,024,997
`5,032,393
`5,107,842
`
`1111970 Duran et al. ............................ 106/197
`3/1979 Fitch et al ............................... 514/975
`4/1982 Puglia et al. .............................. 424/38
`1111982 Peck et al ............................... 514/975
`111984 Munshi ................................... 514/849
`12/1987 Denick et al. . ......................... 424/683
`12/1987 Denick .................................... 514n7o
`1/1988 Denick .................................... 514/974
`8/1988 Denick et al ........................... 514/974
`8/1988 Wright ........................................ 546n
`9/1988 Wright et al ............................ 548/4o3
`1111988 Mody et al ............................. 514/557
`4/1989 Wright et al ............................ 514/819
`8/1989 Mir et al ................................. 424/690
`11/1989 Wright et al ............................ 514/569
`12/1989 Ventouras ................................ 424/469
`1/1990 Amer et al .............................. 514/974
`5/1990 Weibel et al ............................. 536156
`12/1990 Motola et al. . ......................... 514/557
`2/1991 Carlia et al ............................. 514/400
`5/1991 Tai .......................................... 424/493
`6/1991 Motola et al ........................... 514/974
`7/1991 Douglas et al ......................... 514/974
`4/1992 Levene et al. ..................... 128/662.02
`
`W086/06626 1111986 WIPO .
`
`OTHER PUBLICATIONS
`
`Remington's Pharmaceutical Sciences, 18th Ed., Chapter
`83, Solution's, Emulsions, Suspensions and Extracts, pp.
`1519-1530 (1990).
`Avicel® RC/CL Microcrystalline Cellulose and Carboxym(cid:173)
`ethyl Cellulose, NF, Bulletin RC-16. FMC Corp., pp. 1-8
`(1986).
`Chemical Abstracts, vol. 104, No. 8, Abst II 104:52267c,
`pp. 79-80, Feb. 1986.
`Avicel® RC-591 Microcrystalline Cellulose in Emulsions
`and Suspensions, FMC Corp. (1983).
`DiMemo. L.M. et al .• "Rheological and Colloidal Aspects of
`Avicel® Microcrystalline Cellulose", Cellulose its Deriva(cid:173)
`tive, Chapter 47. pp. 511-519 (1985).
`The Physicians Desk Reference, 46th Ed., pp. 1156-1157
`(1992).
`Remington's Pharmaceutical Sciences, 16th ed., (1980) p.
`1247.
`Handbook of Pharmaceutical Excipients, (1986) pp.
`131-133.
`
`Primary Examiner-Raymond J. Henley, ID
`Attorney, Agent, or Finn-Bernard F. Plantz
`ABSTRACT
`
`[57]
`
`The present invention relates to an aqueous pharmaceutical
`suspension composition containing suspended acetami(cid:173)
`nophen and at least one additional pharmaceutical active, a
`suspension system containing xanthan gum, a mixture of
`microcrystalline cellulose and sodium carboxymethylcellu(cid:173)
`lose and an auxiliary suspending agent selected from the
`group consisting of hydroxyethylcellulose and a pharma(cid:173)
`ceutically acceptable salt of carboxymethylcellulose, an
`effective amount of a taste-masking composition; and water,
`as well as a process for producing such aqueous pharma(cid:173)
`ceutical suspensions.
`
`31 Claims, No Drawings
`
`Exhibit 1154
`IPR2017-00807
`ARGENTUM
`
`000001
`
`

`

`5,658,919
`
`1
`AQUEOUS PHARMACEUTICAL
`SUSPENSION AND PROCESS FOR
`PREPARATION THEREOF
`
`This is a continuation of application Ser. No. 08/383,542,
`filed Feb. 3, 1995. now abandoned, which is a continuation
`application of Ser. No. 08/048,701 filed Apr. 16, 1993, now
`abandoned.
`
`FIELD OF THE INVENTION
`
`The present invention relates to aqueous pharmaceutical
`suspensions and, more particularly, to aqueous suspensions
`containing suspended acetaminophen, at least one additional
`pharmaceutical active, a suspending system and a taste(cid:173)
`masking composition. This invention also relates to a pro(cid:173)
`cess for preparing such suspensions.
`
`2
`In view of these difficulties, it would be desirable to
`develop a ready-to-use pharmaceutical suspension, espe(cid:173)
`cially for combination products containing both dissolved
`and suspended solid actives, with a liigh degree of stability
`5 and good taste-masking characteristics. Therefore, there
`exists a need for a liquid dosage form that minimizes
`sedimentation of the suspended active ingredient, provides
`uniform distribution of the dissolved active ingredient and
`has a palatable taste.
`The present invention provides a stable aqueous suspen-
`sion for formulations containing suspended acetaminophen
`and at least one additional pharmaceutical active, which
`when combined with sweeteners and flavoring agents, pro(cid:173)
`vides a palatable liquid dosage form. This dosage form is
`15 also physicochemically stable and especially well suited for
`both geriatric and pediatric applications.
`
`10
`
`BACKGROUND OF THE INVENTION
`
`SUMMARY OF THE INVENTION
`
`Orally administered drugs are provided to the patient in
`many dosage forms, including solid forms such as capsules,
`caplets or tablets and liquid forms such as solutions, emul(cid:173)
`sions or suspensions. Pharmaceuticals administered in solid
`form are usually intended to be swallowed whole. The
`disagreeable taste of the drug is generally not of concern
`when formulating swallowable dosage forms, because the
`pharmaceutical's taste can be easily masked with an exterior
`coating.
`Children. older persons, and many other persons includ-
`ing disabled or incapacitated patients often have trouble
`swallowing tablets or capsules. In these situations, it is
`desirable to provide the drug either in a chewable solid form
`or a liquid form. For many patients. including pediatric and
`geriatric patients. a liquid oral dosage form is preferred over
`a chewable dosage form. A liquid dosage is especially 35
`preferred for this class of patients because of the ease with
`which it may be swallowed. Additionally, patients may be
`more inclined to comply with their medication instruction if
`the dosages are easier to ingest.
`However. a common problem associated with liquid phar- 40
`maceutical dosage forms is the often disagreeable taste of a
`drug that may manifest itself when the drug is in the liquid
`dosage form. Sometimes, the taste of the drug in the dosage
`form may be overpowered by adding sweeteners or flavoring
`agents to the formulation. These agents mask the bitter or 45
`unpleasant taste of drugs. However. these agents are not
`totally effective in concealing the unpalatable taste of the
`pharmaceutical.
`Liquid suspension dosage forms have stability problems
`associated with maintaining the drugs in suspension. Poorly 50
`formulated liquid pharmaceutical suspensions allow the
`drug to settle out as a sediment and may not properly
`redisperse, thereby affecting the therapeutic concentration of
`drug in the suspension. This may result in underdosing or
`overdosing of the patient. which may seriously compromise 55
`the patient's recovery.
`If the liquid dosage form is a combination product con(cid:173)
`taining both dissolved and suspended solid pharmaceutical
`actives. one active must remain suspended and the other
`active(s) must be uniformly distributed throughout the com- 60
`position to ensure proper dosing. Additionally, the pharma(cid:173)
`ceutical suspension should be readily pourable so that the
`dosage is easy to administer. The requirement that a phar(cid:173)
`maceutical suspension is readily pourable effectively places
`an upper limit on the viscosity of the suspension. This 65
`limitation also indirectly limits the amount of pharmaceuti-
`cal actives that the suspension will suspend.
`
`The present invention provides a pharmaceutical suspen-
`20 sion containing suspended acetaminophen. at least one addi(cid:173)
`tional pharmaceutical active selected form the group con(cid:173)
`sisting of antitussives, expectorants, antihistamines,
`sympathornimetics and mixtures thereof. a suspending sys(cid:173)
`tem containing xanthan gum. a mixture of microcrystalline
`25 cellulose and sodium carboxymethylcellulose and an auxil(cid:173)
`iary suspending agent selected form the group consisting of
`hydroxyethylcellulose and a pharmaceutically acceptable
`salt of carboxymethylcellulose, and an effective amount of
`a taste-masking composition to provide a palatable taste to
`30 the suspension.
`Another embodiment of this invention provides a process
`for preparing the aqueous pharmaceutical suspension. The
`mixture of microcrystalline cellulose and sodium carboxym(cid:173)
`ethylcellulose is hydrated in an aqueous liquid to form a first
`liquid admixture. The xanthan gum and the auxiliary sus(cid:173)
`pending agent are added to a liquid to form a second liquid
`admixture. The first and second liquid admixtures are com(cid:173)
`bined to form the suspending system. The acetaminophen
`and at least one additional pharmaceutical active are added
`to the suspending system to form the pharmaceutical sus(cid:173)
`pension.
`
`DETAIIED DESCRIPTION OF THE
`PREFERRED EMBODIMENTS
`The present invention provides a novel suspension system
`particularly well suited for use in pharmaceutical suspen(cid:173)
`sions. It is the applicants' discovery that a stable and
`pourable suspension containing acetaminophen and at least
`one additional pharmaceutical active can be formed by
`employing a suspending system of xanthan gum, a mixture
`of microcrystalline cellulose and sodium carboxyrnethylcel(cid:173)
`lulose and an auxiliary suspending agent selected from the
`group consisting of hydroxyethylcellulose and a pharma(cid:173)
`ceutically acceptable salt of carboxyrnethylcellulose.
`By limiting the amount of water in the suspension. the
`amount of acetaminophen dissolved in the suspension can be
`reduced. This reduction in the amount of dissolved acetami(cid:173)
`nophen reduces the need for taste-masking.
`The suspending system forms a very stable and pourable
`suspension when it contains xanthan gum in the range of
`from about 0.1 to about 0.25 gram per 100 rnL of
`suspension, a mixture of microcrystalline cellulose and
`sodium carboxyrnethylcellulose in the range of from about
`0.4 to about 1.0 gram per 100 rnL of suspension and a
`auxiliary suspending agent selected from the group consist(cid:173)
`ing of about 0.01to0.10 gram per 100 rnL of the suspension
`
`000002
`
`

`

`5,658,919
`
`5
`
`3
`of a pharmaceutically acceptable salt of carboxymethylcel(cid:173)
`lulose and about 0.1 to about LO gram per 100 mL of the
`suspension of hydroxyethylcellulose. The weight ratio of
`xanthan gum to microcrystalline cellulose is preferably
`maintained in the range between about a 1:4 to 1:6. Prefer-
`ably the suspending system contains xanthan gum in the
`range of from about 0.13 to about 0.15 gram per 100 mL of
`suspension, a mixture of microcrystalline cellulose and
`sodium carboxymethylcellulose in the range of from about
`0.50 to about 0.75 gram per 100 mL of suspension and a 10
`auxiliary suspending agent selected from the group consist(cid:173)
`ing of about 0.02 to 0.05 gram per 100 mLofthe suspension
`of a pharmaceutically acceptable salt of carboxymethylcel(cid:173)
`lulose and about 0.2 to about 0.5 gram per 100 mL of the
`suspension ofhydroxyethylcellulose. Sodium carboxymeth- 15
`ylcellulose is the preferred auxiliary suspending agent.
`The xanthan gum suitable for use in the present invention
`is a high molecular weight polysaccharide produced by
`Xanthonwnas campestris. Techniques and strains for pro(cid:173)
`ducing this polysaccharide are described in U.S. Pat. Nos. 20
`4.752,580 and 3,485,719 (the disclosures of which are
`hereby incorporated by reference). The xanthan gum used in
`the present invention should have a viscosity in a one
`percent salt solution of from about 1000 to about 1700 cP
`(mPa-sec). The one percent solution's viscosity should be 25
`measured at 25° C. with an LV model Brookfield Synchro(cid:173)
`Lectric viscometer at 60 rpm, no. 3 spindle. Xanthan gum is
`available from several commercial suppliers such a R. T.
`Vanderbilt Company and Kelco, a division of Merck.
`Examples of suitable xanthan gums are KeltrolTM, KeltrolTM 30
`F. KeltrolTM T. KeltrolTM TF and Keltro1Th1 1000 (Keltrol is
`a trademark of Merck Inc.). Keltro1n.1, KeltrolTM TF and
`KeltrolTM 1000 are the xanthan gums preferred for use in
`pharmaceutical suspensions.
`The mixture of microcrystalline cellulose and sodium 35
`carboxymethylcellulose used in the present invention is a
`dried coprecipitated microcrystal of cellulose and sodium
`carboxymethylcellulose. Sodium carbxymethylcellulose is
`commonly used as the coprecipitate in microcrystalline
`cellulose. It is preferable that sodium carboxymethylcellu- 40
`lose comprise in the range of from about 8 weight percent to
`about 19 weight percent of the total weight of the mixture.
`Presently preferred are microcrystalline cellulose products
`having in the range of from about 8 to about 14 weight
`percent sodium carboxymethylcellulose. These mixtures are 45
`commercially available from FMC under the trademark
`Avicel® CL-611, Avicel® RC-581 and Avicel® RC-591.
`Avicel® RC-591 is the preferred mixture of microcrystalline
`cellulose and sodium carboxymethylcellulose for use in the
`suspension. It contains about 8.3 to about 13.8 weight 50
`percent sodium carboxymethylcellulose, with the remainder
`being microcrystalline cellulose.
`The auxiliary suspending agent used in the present inven(cid:173)
`tion is selected from the group consisting of hydroxyethyl(cid:173)
`cellulose and a pharmaceutically acceptable salt of car- 55
`boxymethylcellulose. Suitable pharmaceutically acceptable
`salts of carboxymethylcellulose include sodium and calcium
`salts of a polycarboxymethyl ether of cellulose, commer(cid:173)
`cially available as sodium carboxymethylcellulose, USP and
`calcium carboxymethylcellulose, NF. Sodium 60
`carboxymethylcellulose, USP contains between about
`6.5-7.5% by weight sodium on a dry basis and is commer(cid:173)
`cially available form Aqualon Co. under the product desig(cid:173)
`nation Type 7HOF. The hydroxyethylcellulose is a partially
`substituted poly(hydroxyethyl) ether of cellulose. 65
`Hydroxyethylcellulose, NF is commercially available from
`Aqualon Co. under the tradename NatrosolTM 250L.
`
`4
`The suspending system discussed above is suitable for
`suspending acetaminophen powder in an aqueous solution.
`The particulate solids as a general guideline should have a
`particle diameter in the range of from about 1 micron to
`about 850 microns. Preferably the particle diameter will
`range from about 37 microns to about 420 microns ( 400 to
`40 mesh based on U.S. standard mesh screens). However,
`those skilled in the art will recognize the fact that particle
`size of a speciiic particulate solid should be varied with the
`density of the particulate solid following the guidelines of
`Stokes' Law. The optimum particle size for a suspension
`should be determined empirically based on the end use and
`desired stability of the suspension.
`At least one additional pharmaceutical active is included
`in the suspension of the present invention. This active is a
`pharmaceutical which may be used in combination with
`acetaminophen to form a cold or cough/cold formulation.
`Generally these actives are selected from the group consist(cid:173)
`ing of antitussives, expectorants, antihistamines,
`sympathomimetics, and mixtures thereof.
`Suitable antihistamines include chlorophenirarnine male(cid:173)
`ate terfenadine, astemizole, diphenhydrarnine hydrochloride
`and mixtures thereof. Antitussives suitable for use in the
`present invention include dextromethorphan HBr, diphen(cid:173)
`hydramine hydrochloride and mixtures thereof. Expecto(cid:173)
`rants which may be used in the invention include guaifen(cid:173)
`esin. Sympathomimetics suitable for use in this invention
`include pseudoephedrine hydrochloride, phenytpropanola(cid:173)
`mine and mixtures thereof. Other pharmaceutically accept(cid:173)
`able salts of the aforementioned compounds may also be
`used in the present invention. Additional antitussives.
`expectorants, antihistamines, and sympathomimetics are
`described in Remington's pharmaceutical Sciences, Mack
`Publishing Co., Easton, Pa:, 18th ed., Chapters 42. 43 & 59
`(1990), which is hereby incorporated by reference.
`Preferably, the additional pharmaceutical actives used in
`combination with acetaminophen are pseudoephedrine
`hydrochloride, chlorphenirarnine maleate, and, optionally,
`dextromethorphan hydrobromide. These additional pharma(cid:173)
`ceutical actives are generally in solution in the aqueous
`phase of the suspension.
`The acetaminophen and the additional pharmaceutical
`active(s) are present in the suspension in therapeutic effec(cid:173)
`tive amounts, which are amounts that produce the desired
`therapeutic response upon oral administration and can be
`readily determined by one skilled in the art. In determining
`such amounts, the particular compound being administered.
`the bioavailability characteristics of the pharmaceutical, the
`dose regimen, the age and weight of the patient and other
`factors must be considered.
`Generally the suspension may contain in total up to about
`20 grams of acetaminophen and the additional pharmaceu(cid:173)
`tical active per 100 mL of suspension. The amount of
`pharmaceutical active present in the suspension should be
`sufficient to provide a therapeutic amount of the active and
`a convenient dosage unit.
`The suspension of the present invention may also include
`a taste-masking composition to mask the bitter taste of the
`actives in the composition, particularly the suspended
`acetaminophen. Generally the taste-masking composition
`contains at least one sweetening agent and at least one
`flavoring agent. The flavoring and coloring agents added to
`the mixture should be of the type and amount desired for the
`particular suspension to meet the preferences dictated by the
`intended consumer of such suspension, e.g., pediatric or
`adult.
`
`000003
`
`

`

`5,658,919
`
`10
`
`15
`
`20
`
`5
`Suitable sweetening agents include, but are not limited to,
`sugars such as monosaccharides, disaccharides and polysac(cid:173)
`charides. Examples of suitable sugars include but are not
`limited to xylose, ribose, glucose, mannose, galactose,
`fructose, dextrose, sucrose, maltose, partially hydrolyzed 5
`starch or corn syrup solids, and sugar alcohols such as
`sorbitol, xylitol, mannitol, glycerin and combination thereof.
`Preferred as a sugar sweetener is high fructose corn syrup
`provided as an aqueous solution. The amount of sugar
`sweetener used in the suspension will vary depending on the
`degree of sweetening desired for the particular suspension.
`Generally the amount of sugar sweetener will be in the range
`of from 0 to about 110 grams per 100 mL of the suspension.
`Preferably the amount of sugar sweetener will be in the
`range of from about 40 grams to about 100 grams per 100
`mL of suspension. Water soluble artificial sweeteners also
`may be employed in place of or in addition to sugar
`sweeteners. Examples of suitable artificial sweeteners
`include but are not limited to aspartame, sucralose,
`cyclamates, saccharin and mixtures thereof. The amount of
`artificial sweetener used in the suspension may vary from in
`the range of 0 to about 5 grams per 100 mL of suspension.
`Suitable flavoring agents include natural and/or artificial
`flavors such as mints (i.e., peppermint, etc.,), menthol,
`cinnamon, vanilla, artificial vanilla, chocolate, artificial 25
`chocolate. both natural and/or artificial fruit flavors (i.e.,
`cherry, grape, orange, strawberry, etc.,) and combinations of
`two or more thereof. Flavoring agents are generally provided
`as a minor component of the suspension in amounts effective
`to provide a palatable flavor to the suspension. However, 30
`flavoring agents are generally present in the suspension in
`amounts in the range of from 0 to about 5 grams per 100 mL
`of the suspension.
`Optimum masking of the taste of the solid pharmaceutical
`active in the suspension can be achieved by limiting the 35
`amount of water in the suspension. As a minimum, the
`amount of water present in the suspension may be limited to
`that amount necessary to hydrate the mixture of microcrys(cid:173)
`talline cellulose and sodium carboxymethylcellulose. The
`minimum amount of water also must provide the suspension 40
`with a sufficient aqueous base to impart the desired degree
`of viscosity. It is preferred for taste-masking of bitter
`pharmaceutical( s) that the total amount of water contained in
`the suspension be in the range of from about 25 to about 60,
`preferably about 30 to about 55. grams per 100 mL of 45
`suspension.
`The preferred pH of the suspension should range from
`about 3 to about 7. The suspension can be buffered to
`maintain the pH of the suspension in the desired pH range.
`Suitable buffers that are not chemically reactive with the 50
`other ingredients may be present in the suspension in
`amounts sufficient to provide the desired degree of pH
`buffering. Preferably the buffers will be present in the range
`of from 0 to 1 gram per 100 mL of the suspension.
`Wetting agents also may be employed in the inventive 55
`suspension to facilitate the dispersion of hydrophobic phar(cid:173)
`maceutical actives. The concentration of wetting agents in
`the suspension should be selected to achieve optimum
`dispersion of the pharmaceutical active within the suspen(cid:173)
`sion with the lowest feasible concentration of wetting agent. 60
`It should be appreciated that an excess concentration of
`wetting agent may cause the suspension to flocculate. Those
`skilled in the art are well versed in suitable empirical
`methods to determine the appropriate wetting agents and
`concentrations to achieve optimum dispersion and avoid 65
`flocculation. Suitable wetting agents are listed in the U.S.
`Pharmacoepia XXL
`
`6
`Preservatives useful in the present invention include but
`are not limited to sodium benzoate, potassium sorbate, salts
`of edetate (also known as salts of ethylenediaminetetraacetic
`acid, or EDTA, such as disodium edetate) and parabens
`(such as methyl, ethyl, propyl and butyl p-hydroxybenzoic
`acids esters). The preservatives listed above are exemplary,
`but each preservative must be evaluated on an empirical
`basis, in each formulation, to assure the compatibility and
`efficacy of the preservative. Methods for evaluating the
`efficacy of preservatives in pharmaceutical formulations are
`known to those skilled in the art. Sodium benzoate and
`butylparaben are the presently preferred preservative ingre(cid:173)
`dients to add to a pharmaceutical suspension containing
`acetaminophen although other pharmaceutically acceptable
`preservatives may be substituted therefor.
`Preservatives are generally present in amounts of up to 1
`gram per 100 mL of the suspension. Preferably the preser(cid:173)
`vatives will be present in amounts in the range of from about
`0.15 to about 0.5 gram per 100 mL of the suspension. For
`pharmaceutical suspensions containing acetaminophen it is
`preferred that the preservative sodium benzoate be present in
`the range of from about 0.1 to about 0.3 gram per 100 mL
`of the suspension and butylparaben be present in the range
`of from about 0.01 to about 0.05 gram per 100 mL of the
`suspension. It is most preferred that sodium benzoate be
`present at a concentration of 0.2 gram per 100 mL of the
`suspension and butylparaben be present at a concentration of
`0.025 gram per 100 mL of the suspension.
`Coloring agents also may be incorporated in the suspen(cid:173)
`sion to provide an appealing color to the suspension. The
`coloring agents should be selected to avoid chemical incom(cid:173)
`patibilities the other ingredients in the suspension. Suitable
`coloring agents for use in pharmaceutical suspensions are
`well known to those skilled in the art.
`The suspensions also may contain one or more of the
`following additives defoarning agents, surfactants; electro(cid:173)
`lytes (monovalent cations are currently preferred); and
`sequestering agents.
`As one embodiment of the present invention, hereinafter
`is provided a cold and a cough/cold pharmaceutical suspen(cid:173)
`sion containing acetaminophen. The following formulation
`provides a stable suspension that is pourable and has supe(cid:173)
`rior taste-masking characteristics:
`
`TABLE 1
`
`Cold and Cough/Cold Suspension'
`
`Broad Range
`(g/100 mL)
`
`Preferred Range
`(g/100 mL)
`
`Suspending System
`
`XanthanGum
`Microcrystalline
`Cellulose/Sodium
`Carboxymethyl-
`Cellulose Mixture
`Sodium Carboxy-
`methylcellulose or
`Hydroxyethyl-
`cellulose
`Actives
`
`Acetaminophen
`Pseudoephedrine HCI
`Chloropheniramine
`Maleate
`Dextromethorphan
`HBr2
`
`0.1-0.25
`0.4-1
`
`0.13-0.15
`0.50-0.75
`
`0.01-0.1
`
`0.02-0.05
`
`0.1-1.0
`
`0.2-0.5
`
`1-15
`0.1-1
`0.01-0.07
`
`0.05-0.5
`
`3.2-10
`0.3-0.94
`0.02-0.07
`
`0.1-0.32
`
`000004
`
`

`

`5,658,919
`
`7
`
`TABLE 1-continued
`
`Cold and Cough/Cold Suspension'
`
`Other Ingredients
`
`High Fructose Corn
`Syrup3
`Sorbitol Solution•
`Glycerin
`Flavoring
`Purified Water
`Coloring
`Sodium Benzoate
`Butylparaben
`Citric Acid
`Propylene Glycol
`MalicAcid
`
`Broad Range
`(g/100 mL)
`
`Preferred Range
`(g/100 mL)
`
`50--90
`
`60--90
`
`1-30
`1-20
`0.01-1
`10--30
`0.001-.05
`0.1--0.3
`0.01--0.05
`0.03--0.20
`0.1--0.5
`0.05--0.18
`
`10--25
`5-12
`0.01--0.3
`15-25
`0.002--0.02
`0.15--0.3
`0.02--0.03
`0.03--0.12
`0.15--0.35
`0.06--0.12
`
`1 All measurements in this table are listed in grans per 100 mL of suspension
`as measured at 25° C. If the volume of all the components does not equal 100
`mL, the additional volume may be provided by the addition of high fructose
`corn syrup.
`21be dextromethorphan HBr is omitted in the cold formulation.
`"The solids content of high fructose com syrup is approximately 77% by
`weight, of which 55% by weight is fructose.
`.
`.
`4ThC sorbitol solution is approximately 70% by weight sorb1tol.
`
`20
`
`8
`vatives could also be used in the suspension. The acetami(cid:173)
`nophen suspension should contain in the range of from about
`0.01 to about 0.05 gram of butylparaben per 100 rnL of
`suspension and in the range of from about 0.1 to about 0.3
`5 gram of sodium benzoate per 100 rnL of suspension.
`The coloring agent present in the acetaminophen suspen(cid:173)
`sion are FD&C Red #40, FD&C Blue #1 and D&C Red #33.
`Other coloring agents can be used in the pharmaceutical
`suspension.
`10 When preparing the pharmaceutical suspensions provi.ded
`herein, the mixture of rnicrocrystalline cellulose and sodium
`carboxymethylcellulose, xanthan gum, and the auxiliary
`suspending agent are adequately dispersed and hydrated to
`provide the desired rheological characteristic to the suspen(cid:173)
`sion. Hydrating the mixture of rnicrocrystalline cellulose
`15 and sodium carboxymethylcellulose requires high shear
`mixing to disperse and hydrate the particles. Examples of
`suitable high shear mixing devices include Scott Turbon
`mixers. homogenizers and colloid mills. It is preferred that
`the mixture of rnicrocrystalline cellulose and sodium car(cid:173)
`boxymethyl cellulose be fully dispersed in an aqueous
`liquid, such as the purified water, USP or a mixture of the
`sorbitol solution and purified water. USP. prior it mixing
`with other ingredients.
`The xanthan gum and the auxiliary suspending agent also
`25 should be dispersed in a liquid prior to mixing with the
`ingredients of the suspension, but they do not require high
`shear mixing. Suitable dispersing liquids include purified
`water, USP or one of the sweetening agents, such as glyc-
`erin.
`The xanthan gum and the auxiliary suspending agent
`liquid admixture is generally combined with the rnicrocrys(cid:173)
`talline cellulose and sodium carboxymethyl cellulose aque(cid:173)
`ous admixture to form the suspending system before the
`addition of other dry components, such as the
`acetaminophen, other pharmaceutical actives, buffers. pre(cid:173)
`servatives or colorings. When adding pharmaceutical actives
`of more limited solubility, such as dextromethorphan HBr, it
`is useful to dissolve the active in one of the other compo(cid:173)
`nents of the composition before it is added to the suspending
`system. For example. dextromethorphan HBr may be dis(cid:173)
`solved in the propylene glycol before it is added to the
`suspending system. If, however, the pharmaceutical active is
`very soluble in the water, e.g., chloropheniramine maleate,
`it may be added to the composition earlier in the manufac(cid:173)
`turing process, such as after the hydration of the mixture of
`rnicrocrystalline cellulose and sodium carboxymethylcellu(cid:173)
`lose.
`To assure even dispersion of the other ingredients the
`addition of the other ingredients into the suspension should
`be performed in a stepwise manner. The mixing should be
`50 conducted in a manner that does not entrain excess air.
`However if excess air is entrained in the suspension. after
`the suspension is brought to its final volume, it may be
`deaerated to remove entrained air and thereby returned to its
`normal density. The final volume of the suspension ingre(cid:173)
`dients listed above may not provide a total volume of 100
`rnL. The final volume may be brought to 100 rnL by the
`addition of water or preferably one or more liquid sugar
`sweeteners. For taste-masking purposes it is currently pre(cid:173)
`ferred to use liquid sugar sweetener such as high fructose
`60 corn syrup or sorbitol to bring the suspension to its final
`volume.
`A more detailed example of the preferred process of the
`invention is provided in the following examples section.
`
`30
`
`The acetaminophen added to the suspension should be
`provided in a particulate form having a particle size range
`which permits greater than 99 percent of the particle to pass
`through a 40 mesh screen (U.S. standard screen). The
`amount of acetaminophen added to the suspension should be
`sufficient to provide a therapeutic amount of acetaminophen
`in a convenient dosage unit. The amount of acetaminophen
`in suspension should be in the range of from about 1 to about
`15 grams per 100 rnL of suspension.
`The pseudoephedrine HCl, chloropheniramine maleate 35
`and dextromethorphan HBr used in the suspension are USP
`grade. They are added in amounts to provide a therapeutic
`effect in a convenient dosage form.
`The preferred sweeteners for acetaminophen suspension
`are high fructose corn syrup, sorbitol and glycerin. The high 40
`fructose corn syrup should be provided as an aqueous
`solution containing 77% by weight solids, of which 55% by
`weight is fructose. The amount of aqueous high fructose
`corn syrup percent in the acetaminophen suspension should
`be in the range of from about 50 to about 90 grams per 100 45
`rnL of suspension. The sorbitol also should be present as an
`aqueous solution containing 70% sorbitol by weight. The
`amount of aqueous sorbitol present in the acetaminophen
`suspension should be in the range of from about 1 to about
`30 gr