|HAO WANAT HA MARIAUS009827320B2 DE EL ANIMATION WITH (12 ) United States Patent (10 ) Patent No. : US 9 ,827 , 320 B2 Lin et al. ( 45 ) Date of Patent: * Nov . 28 , 2017 (54 ) COMPOSITIONS WITH REDUCED BITTER (58 ) Field of Classification Search TASTE PERCEPTION None See application file for complete search history . @(71 ) Applicant: The Procter & Gamble Company , Cincinnati , OH (US ) ( 56 ) References Cited @(72 ) Inventors : Yakang Lin , Liberty Township , OH U . S . PATENT DOCUMENTS (US ) ; Koti Sreekrishna , Mason , OH 6 , 169 ,118 B1 * 1/ 2001 Bilali A61K 8 / 21 ( US ) 424 /401 2005/ / 01531350153135 A1 ** 7 / 2005 2005 Popplewell ...... A61KA61K 8 // 11 @( 73 ) Assignee : The Procter & Gamble Company , 428 /402 . 2 Cincinnati , OH (US ) 2009 /0018213 A1 * 1 / 2009 Snyder ...... A01N 31/ 02 514 /724 @( * ) Notice : Subject to any disclaimer, the term of this 2013/ 0243935 A1 9 / 2013 Barnekow et al. patent is extended or adjusted under 35 U . S . C . 154 ( b ) by 0 days. FOREIGN PATENT DOCUMENTS This patent is subject to a terminal dis EP 2438907 A2 4 / 2012 claimer . WO WO 98 /03153 AL 1 / 1998 WO WO 98 /05312 AL 2 / 1998 (21 ) Appl. No. : 14 /633 , 161 ( 22 ) Filed : Feb . 27, 2015 OTHER PUBLICATIONS U .S . Appl . No. 14 /633 , 160 . * (65 ) Prior Publication Data U . S . Appl. No. 14 /633 , 163 . * Product Data Sheet for Mirapol A - 15 , downloaded Feb . 2 , 2017 , US 2015 /0238613 A1 Aug . 27 , 2015 from http :/ /dewolfchem . com / wp -content / uploads/ 2013 /08 /mirapol a15 .pdf . * Related U . S . Application Data International Search Report and Written Opinion for 13580 — PCT / (60 ) Provisional application No .62 / 065 ,846 , filed on Oct . US2015 /017896 dated Jun . 15 , 2015 . 20 , 2014 , provisional application No . 61/ 945 , 437 , Rhodia : “Mirapol A - 15 Product Data Sheet ” , Sep . 1, 2008 , http :/ / filed on Feb . 27 , 2014 . dewolfchem . com / wp -content / uploads / 2013 /08 /mirapol - a15 .pdf . (51 ) Int. Cl. * cited by examiner A61K 47134 ( 2017 .01 ) A61K 8 / 84 ( 2006 . 01 ) Primary Examiner — Frederick Krass A61K 8 /88 ( 2006 .01 ) Assistant Examiner — Michael P Cohen A23L 1 /22 ( 2006 .01 ) (74 ) Attorney , Agent, or Firm — Amanda Herman ; A23L 2 /56 ( 2006 . 01 ) Alexandra S . Anoff A610 11 / 00 ( 2006 .01 ) A23L 27 /00 ( 2016 . 01 ) (57 ) ABSTRACT (52 ) U . S . CI. A composition with reduced bitterness containing poly CPC ...... A61K 47 / 34 ( 2013 .01 ); A23L 2/ 56 quaternium - 2 , polyquaternium - 17 , and /or polyquaternium ( 2013 .01 ) ; A23L 27/ 86 ( 2016 .08 ) ; A6IK 8 /84 18 . ( 2013 .01 ); A61K 8 /88 ( 2013 .01 ); A610 11/ 00 (2013 .01 ) ; A6IK 2800 / 5426 (2013 .01 ) 11 Claims, 14 Drawing Sheets U . S . Patent Novcom . 28, 2017 wwwSheet 1 of 14 . com US 9, 827 ,320 B2
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coö o todo on Bitterness US 9 ,827 ,320 B2 COMPOSITIONS WITH REDUCED BITTER FIG . 2B compares the modulation of bitterness of solu TASTE PERCEPTION tions with different water soluble polymers in an Assay for Taste Receptors ; FIELD OF THE INVENTION FIG . 2C compares the modulation of bitterness of solu 5 tions with different water soluble polymers and actives in an The present invention relates to a composition comprising Assay for Taste Receptors ; a low molecular weight polyquaternium to modulate bitter FIG . 3 compares the modulation of bitterness of different ness, more particularly a low level of polyquaternium - 2 , strains of hops with polyquaternium - 2 in an Assay for Taste polyquaternium -17 , and/ or polyquaternium - 18 to modulatedulate Receptors ; 10 FIG . 4A compares the modulation of bitterness of solu bitterness . tions containing a composition and a concentration of poly BACKGROUND OF THE INVENTION quaternium - 2 in an Assay for Taste Receptors ; FIG . 4B compares the modulation of bitterness of solu There are five recognized taste sensations, sweet, salty , tions containing a composition and a concentration of poly sour, bitter, and umami. Many people dislike things that are 15 quaternium - 2 in an Assay for Taste Receptors ; overly bitter and perceive it is as unpleasant, sharp , or FIG . 4C compares the modulation of bitterness of solu otherwise disagreeable . Bitterness is the most sensitive of tions containing a composition and a concentration of poly the tastes and it is thought to be a defense mechanism to quaternium - 2 in an Assay for Taste Receptors ; protect the body against ingestion of toxic substances, as a FIG . 5A compares the modulation of bitterness of solu large number of natural bitter compounds are known to be 20 tions containing a composition and a concentration of poly toxic . quaternium - 2 in an Assay for Taste Receptors ; However some components that are commonly found in FIG . 5B compares the modulation of bitterness of solu foods, beverages, pharmaceuticals , and oral care composi- tions containing a composition and a concentration of poly tions can have a bitter taste . Sweeteners , salt (including quaternium - 2 in an Assay for Taste Receptors ; sodium chloride ), and flavors are commonly used to mute 25 FIG . 5C compares the modulation of bitterness of solu the bitterness in these compositions. Despite these efforts, tions containing a composition and a concentration of poly many compositions still possess an unpleasant taste and /or quaternium - 2 in an Assay for Taste Receptors ; after taste . This causes some consumers to avoid and / or FIG . 6 compares the modulation of bitterness of full dislike taking the composition . formulations containing one or more actives and excipients Thus, there is a need for a composition with reduced 30 in an Assay for Taste Receptors ; bitterness. FIG . 7 shows the Descriptive Profile Panel (DPP ) bitter intensity of six different compositions containing a high SUMMARY OF THE INVENTION fructose corn syrup (HFCS ) base and different concentra tions of polyquaternium - 2 ; and A composition with reduced bitterness comprising a poly - 35 FIG . 8 shows the Descriptive Profile Panel (DPP ) bitter quaternium selected from the group consisting of poly - intensity of two examples that both contain four actives and quaternium -2 , polyquaternium - 17 , polyquaternium - 18 , and one example contains polyquaternium - 2 . combinations thereof. A composition with reduced bitterness comprising : (b ) a DETAILED DESCRIPTION OF THE polyquaternium selected from the group consisting of poly - 40 INVENTION quaternium - 2 , polyquaternium - 17 , polyquaternium - 18 , and combinations thereof; and (b ) a bitter component selected Compositions, including many foods, beverages , medi from the group consisting of Hops, guaifenesin , phenytoin , cines , and oral care composition , have a bitter taste associ omeprazole , cetirizine , jambu , acetaminophen , methyl a ted with them . It has been surprisingly found that poly formyl anthranilate , 2 - aminoacetophenone , methyl anthra - 45 quaternium - 2 can significantly modulate the bitterness in nilate, dimethyl anthranilate , beta - terpineol, beta - naphthyl these compositions . anthranilate , and benzoyl anthranilic acid , 1 , 10 - phenanthro Several polymers , including other polyquats , were tested line, saccharin , and propylene glycol, benzamide , brucine , in vitro taste bud cell assays to determine whether they may 1 , 10 - phenanthroline , and combinations thereof. serve as a bitter blocker. Polyquaternium - 2 modulated the 50 bitterness of guaifenesin (GG ) in the cell assays better than BRIEF DESCRIPTION OF THE DRAWINGS any other polymer, including the polyquats which have a similar chemical structure . Polyquaternium - 17 and /or poly While the specification concludes with claims particularly quaternium -18 are structurally analogous to polyquater pointing out and distinctly claiming the subject matter of the nium - 2 and can be used instead of or in combination with present invention , it is believed that the invention can be 55 polyquaternium - 2 . GG , a drug used in over - the - counter more readily understood from the following description medication , was selected as a compound for screening bitter taken in connection with the accompanying drawings , in blockers because it is known for being exceptionally bitter which : and difficult to taste mask with sweeteners and flavors . FIG . 1A shows the molecular structure for polyquater - Surprisingly , it has been found that polyquaternium - 2 can nium - 2 ; 60 modulate the bitterness in many compositions . In some FIG . 1B shows the molecular structure for polyquater examples , the polyquaternium - 2 can be included in the nium - 17 ; composition at less than about 0 . 2 % . FIG . 1C shows the molecular structure for polyquater - All percentages and ratios used hereinafter are by weight nium - 18 ; of total composition , unless otherwise indicated . All per FIG . 2A compares the modulation of bitterness of solu - 65 centages, ratios, and levels of ingredients referred to herein tions with different water soluble polymers in an Assay for are based on the actual amount of the ingredient, and do not Taste Receptors ; include solvents , fillers , or other materials with which the US 9 , 827 , 320 B2 ingredient may be combined as a commercially available over -the - counter medications, behind - the - counter medica product , unless otherwise indicated . tions and combinations thereof. In some examples , a medi All measurements referred to herein are made at 25° C . cation can be a supplement. ( . e . room temperature ) unless otherwise specified . As used herein , the articles “ a ” and “ an ” are understood The composition can contain , consist of, or consist essen - 5 to mean one or more of the material that is claimed or tially of, the essential elements and limitations of the inven - described , for example , " an active” or “ a solvent " . tion described herein , as well as any additional or optional The compositions of the present invention can contain , ingredients , components , or limitations described herein or consist of, or consist essentially of, the essential elements otherwise useful in compositions. and limitations of the invention described herein , as well as As used herein , the word “ include ,” and its variants , are any additional or optional ingredients , components , or limi intended to be non - limiting , such that recitation of items in tations described herein or otherwise useful in dosage forms a list is not to the exclusion of other like items thatmay also intended for use or consumption by humans . be useful in the materials , compositions, devices , and meth - It has been found that polyquaternium - 2 can be added to ods of this invention . 15 compositions to reduce bitterness. Polyquaternium - 2 has the As used herein , the word “ or ” when used as a connector CAS Registry Number 68555 -36 - 2 and the chemical name of two or more elements is meant to include the elements is Poly [bis ( 2 - chloroethyl) ether- alt - 1 , 3 -bis [ 3 - ( dimethyl individually and in combination ; for example X or Y , means amino )propyl ] urea ] and is commercially available as X or Y or both . Mirapol® A 15 (available from Rhodia , Cranbury , N . J .) . The By “ oral care composition " , as used herein , is meant a 20 molecular structure for polyquaternium - 2 is shown in FIG . product , which in the ordinary course of usage , is not 1A . Polyquaternium - 17 (CAS Registry Number 148506 -50 intentionally swallowed for purposes of systemic adminis - 7 ) and polyquaternium - 18 (CAS Registry Number 113784 tration of particular therapeutic agents , but is rather retained 58 -0 ) are structurally analogous to polyquaternium - 2 and in the oral cavity for a time sufficient to contact dental can be used in addition to or instead of polyquaternium - 2 to surfaces or oral tissues . Examples of oral care compositions 25 modulate bitter. The molecular structure for polyquater can include dentifrice , mouth rinse , mousse , foam , mouth nium - 17 is shown in FIG . 1B and the molecular structure for spray , lozenge , chewable tablet , chewing gum , tooth whit - polyquaternium - 18 is shown in FIG . 1C . ening strips, floss and floss coatings, breath freshening FIG . 2A compares the modulation of bitterness of a dissolvable strips , or denture care or adhesive product. The control solution comprising 2 mM guaifenesin (GG ) with oral care composition may also be incorporated onto strips 30 solutions comprising 2 mM GG and one of seven water or films for direct application or attachment to oral surfaces . soluble polymers at concentrations ranging from 0 . 33 % to The term " dentifrice” , as used herein , includes tooth or 0 .01 % . The results for FIG . 2 are from an in vitro Assay for subgingival- paste , gel, or liquid formulations unless other - Taste Receptors , as described hereafter . The cell cultures and wise specified . The dentifrice composition may be a single assays provide an in vitro method to screen for bitterness phase composition or may be a combination of two or more 35 that can mimic an in vivo response . separate dentifrice compositions . The dentifrice composition The water soluble polymers that were tested were as may be in any desired form , such as deep striped , surface follows at concentrations ranging from 0 . 01 % to 0 .33 % : striped , multilayered , having a gel surrounding a paste , or Polyquaternium - 6 commercially available as Mirapol® any combination thereof. Each dentifrice composition in a 100 [CAS # 26062 - 79 - 3 ] (available from Rhodia , Cran dentifrice comprising two or more separate dentifrice com - 40 bery , N . J . ) positions may be contained in a physically separated com Polyquaternium - 2 commercially available as Mirapol® A partment of a dispenser and dispensed side - by - side . 15 [CAS # 68555 - 36 - 2 ] (available from Rhodia , Cran As used herein , " dose ” refers to a volume of medication , bury, N . J .) such as liquid medication , containing an amount of a drug Polyquaternium - 7 commercially available as Mirapol® active suitable for administration on a single occasion , 45 550 [ 26590 - 05 - 6 ] ( available from Rhodia , Cranbury, according to sound medical practice . A dose can be orally N . J. ) administered . In one example , a dose can be about 30 mL , Polyquaternium - 7 commercially available as MerquatTM in another example about 25 mL , in another example about 2200 [ CAS # 26590 -05 -6 ] (available from Lubrizol, 20 mL, in another example about 15 mL , and in another Deer Park , Tex . ) example about 10 mL . In another example, a dose of liquid 50 Polyquaternium - 16 commercially available as Luviquat® medication can be from about 10 mL to about 75 mL , in FC550 [CAS # 95144 - 24 - 4 ] (available from BASF, Flo another example from about 15 mL to about 50 mL , in rham Park , N . J . ) another example from about 25 mL to about 40 mL , and in Polyquaternium D16 commercially available as Luvi another example from about 28 mL to about 35 mL. The quat® FC 905 [CAS # 95144 - 24 - 4 ] ( available from concentration of active ingredients can be adjusted to pro - 55 Crescent Company , Islandia , N . Y . ) vide the proper doses of actives given the liquid dose size . Polyquaternium - 44 commercially available as Luviquat® In one example , the dose is intended to be administered care polymer [CAS # 150599 - 70 - 5 ] (available from every 4 hours, in another example every 6 hours, in another BOC Sciences , Shirley, N . Y . ) example every 8 hours, and in another example every 12 The taste receptors were activated as described in the hours . 60 Assay for Taste Receptors herein . The observed activation is As used herein , “ ingestible ” refers to a composition that presented as a % of the control value . The control value is is deliverable to a mammal in need via the oral cavity activation by a 2 mM GG solution with no added polymers . including the mouth and throat or nasal passage , and com The results from this assay showed that only Polyquater binations thereof. In some examples , the composition can be nium - 2 completely blocked the activation of taste cell recep ingestible and swallowable . 65 tors by GG . This is especially surprising, since GG is one of As used herein , “ medication ” refers to medications, such the most bitter actives used in liquid medications . Other as pharmaceuticals , including prescription medications, polymers , including polyquaternium -6 and polyquaternium US 9 ,827 ,320 B2 D16 (Luviquat® 905) also showed some reduction , however to about 0 .5 % , and in another example the modulation was not dose dependent. about 0 . 2 % . The composition can contain alpha hops and / or FIG . 2B compares the modulation of bitterness of a beta hops. solution comprising 2 mM GG with one of four water In one example polyquaternium -2 , polyquaternium - 17 , soluble polymers at concentrations ranging from 0 .01 % to 5 and / or polyquternium - 18 can reduce the overall bitterness of 0 . 00003 % . The four water soluble polymers were poly - a composition by at least about 5 % as compared to an quaternium - 6 (Mirapol® 100 ) , polyquaternium - 2 (Mi - identical composition without the polyquaternium - 2 , poly rapol® A15 ) , polyquaternium D16 (Luviquat® FC 550 ), and quaternium - 17 , and / or polyquternium - 18 as determined by polyquaternium D16 (Luviquat® FC 905 ) . The same Assay the in vitro Assay for Taste Receptors as described hereafter, for Taste Receptor Method described herein and for FIG . 2 10 in another example by at least about 10 % , in another was used to generate the results for FIG . 3 . The lower example by at least about 20 % , in another example by at concentrations of polymer were selected to help further least about 30 % , in another example by at least about 40 % , differentiate the potential ability for the polymers to provide in another example by at least about 50 % , in another bitter blocking in vivo . example by at least about 60 % , in another example by at Again , polyquaternium - 2 provided the greatest reduction least about 65 % , in another example by at least about 70 % , in bitterness of the 2 mM GG solution . At 0 .01 % , the in another example by at least about 75 % , in another bitterness was reduced to less than 20 % of the bitterness of example by at least about 80 % , in another example by at the control. Furthermore, polyquaternium - 2 was the only least about 85 % , in another example by at least about 90 % , composition that showed dose dependent blocking . 20 in another example at least about 93 % , in another example FIG . 2C compares the modulation of bitterness of a at least about 95 % , in another example by at least about solutions containing different substances that are known to 97 % , in another example by at least about 98 % , in another be bitter with 0 . 17 % polyquaternium - 2 (Mirapol® A 15 ) , example by at least about 99 % and in another example by at polyquaternium - 7 (MerquatTM 2200 ) , and polyquaternium least about 100 % . 44 (Luviquat® Care Polymer ). The Assay for Taste Receptor 25 In another example , the composition can have an overall Method described herein and was used to generate the bitterness of less than about 8000 fluorescence units ( FUS) results for FIG . 2C . The substances that were tested were 1 as determined by the in vitro Assay for Taste Receptors as mM clofedanol, 1 mM diphenhydramine, 1 mM GG , 1 mM described hereafter , in another example less than about 7500 naproxen , 1 mM ibuprofen , 1 mM quinine , 0 . 1 mM thymol, FUs, in another example less than about 70000 FUs, in APR 30 another example less than about 6500 FUs, in another 100 UM AITC (Allyl Isothiocyanate ) , 100 UM APB 30 example less than about 6000 FUs, in another example less ( 2 - Aminoethoxydiphenyl borate ), 100 uM carvacrol, and 10 than about 5500 FUs, in another example less than about uM ionomycin . 5000 FUs, in another example less than about 4500 FUs, in Surprisingly , the polyquaternium - 2 blocked all but three another example less than about 4000 FUs, in another of the known bitter molecules , whereas the higher molecular 35za example less than about 3500 FUs, in another example less weight polyquats , polyquaternium -7 , and polyquaternium than about 3000 FUs, in another example less than about 44 , did not show bitter blocking. Instead the polyquater 2500 FUs , in another example less than about 2000 FUs, in nium - 7 , and polyquaternium - 44 caused an increase in the another example less than about 1500 FUs, in another bitter response relative to each bitter molecule , as shown by example less than about 1000 FUs, in another example less the higher fluorescence units (FUS ) . 40 than about 750 FUs, in another example less than about 500 Since polyquaternium - 2 was effective in blocking the FUs, in another example less than about 350 FUs, in another bitterness in the Assay for Taste Receptors , it was desirable example less than about 300 FUs, in another example less to understand if polyquaternium - 2 was effective against than about 250 FUs, in another example less than about 200 other bitter agents . As shown in FIG . 3 , it was found that FUs, in another example less than about 150 FUs, in another polyquaternium - 2 was also effective at blocking bitterness 45 example less than about 100 FUs, and in another example from hops in the Assay for Taste Receptors. less than about 50 FUS. FIG . 3 compares the modulation of bitterness of solutions However , it has been surprisingly discovered that poly containing a strain of hops at different concentrations rang - quaternium - 2 does not modulate the bitterness for all com ing from 0 . 000047 % to 0 . 000374 % . Each strain of hops was pounds that are known to be bitter. For instance , FIGS. 4A , tested with the addition of 0 .01 % polyquaternium - 2 . The 50 4B , and 4C compare the modulation of bitterness , if any, of following strains of hops were tested : B - BL168003 , solutions containing an active and a concentration of poly CB -RS5698A - L , CB -RS5722B , and CB -RS5698A - s . All quaternium - 2 . The concentration of polyquaternium - 2 strains of hops used in this example are commercially ranges from 0 .00041 % to 0 . 1 % . GG at a concentration of 2 available from available from Hopsteiner® , Yakima, Wash . mM without polyquaternium - 2 is used as a control. The 2 mM GG was used as a control to make sure that the bitter 55 actives were selected because they are frequently used in cells were registering bitterness . The results for FIG . 3 are medications and are known to be bitter . The results for FIGS . from an in vitro Assay for Taste Receptors as described 4A , 4B , and 4C are from an in vitro Assay for Taste hereafter. Receptors as described hereafter. Surprisingly , as seen in FIG . 3 , 0 .01 % polyquaternium - 2 FIG . 4A compares the modulation of bitterness, if any, of can significantly reduce the bitterness of all four strains of 60 solutions comprising 250 uM active and a concentration of hops . At many concentrations and strains, the bitterness was polyquaternium - 2 . The actives in FIG . 4A are dicyclomine , not detectable by the bitter cells, which could mimic an in hydroxyzine , promethazine , doxepin , and 2 mM GG . FIG . vivo response . 4A shows that polyquaternium - 2 has at best a very weak In one example , the composition can contain from about bitter blocking activity on dicyclomine, hydroxyzine, pro 0 . 0001 % to about 5 % hops, in another example from about 65 methazine , and doxepin . However, FIG . 4A does not show 0 .001 % to about 2 . 5 % , in another example from about a dose dependent effect and thus polyquaternium - 2 is prob 0 .01 % to about 1 % , in another example from about 0 . 05 % ably not a specific blocker of these compositions. US 9 ,827 , 320 B2 The actives in FIG . 4B are 1 mM diltiazem , 2 mM described hereafter. The compositions tested were methyl phenytoin , and 1 mm diphenhydramine Polyquaternium - 2 formyl anthranilate , 2 -aminoacetophenone , methyl anthra blocked some of the bitterness of diltiazem , but it doesn 't nilate , dimethyl anthranilate , beta - terpineol, beta -naphthyl show a dose dependent effect and thus polyquaternium - 2 is anthranilate , benzoyl anthranilic acid , hesperidin , 2 - phe probably not a specific blocker for diltiazem . Polyquater - 5 noxyethanol, para - vanillyl alcohol, and methyl ethoxypyra nium - 2 strongly blocked the bitterness from phenytoin and zine . 2 . 5 mM acetaminophen ( APAP ), 2 mM GG , and 10 uM omeprazole and polyquaternium - 2 had little or no effect on Ionomycin , calcium salt ( commercially available from Life diphenhydramine . Technologies, Grand Island , N . Y ., catalog # 1 - 24222 ) were The actives tested in FIG . 4C included 1 mM cetirizine , used as the controls . In FIG . 5A , 0 .02 % polyquaternium - 2 1 mM enalapril, 0 . 25 % jambu ( Acmella oleracea ) extract 10 substantially modulated or completely modulated the bitter ( commercially available as Jambu SE WS from NaturexTM ness from all of the components . This is true for composi South Hackensack , N . J .) , and 10 mM acetaminophen tions that are particularly bitter , for instance over 6000 FUS, ( APAP ). Polyquaternium - 2 blocked someof the bitterness of like methyl formyl anthranilate , 2 - aminoacetophenone, cetirizine . Polyquaternium - 2 did not show a dose dependent methyl anthranilate , dimethyl anthranilate , beta -terpineol , bitter blocking of enalapril . However, polyquaternium - 2 15 beta -naphthyl anthranilate , and benzoyl anthranilic acid shows a strong dose dependent effect on blocking jambu and where the bitter was completely or substantially modulated APAP. in the Assay for Taste Receptors . Polyquaternium - 2 , polyquaternium - 17 , and /or poly - FIG . 5B compares the modulation of bitterness , if any , of quaternium - 18 can be added to compositions , in particular solutions containing a composition and 0 .01 % polyquater oral care compositions, medicines , and / or ingestible com - 20 nium - 2 in the in vitro Assay for Taste Receptors as described positions. In one example , the composition contains from hereafter . The compositions tested were 5 mM pseu about 0 .01 % to about 1 % polyquaternium - 2 , polyquater - doephedrine hydrochloride , 2 mM terpin , 2 . 5 mM predni nium - 17 , and / or polyquaternium - 18 , in another example solone , 2 .5 mM famotidine, 0 . 5 mM 1 , 10 - phenanthroline , from about 0 .03 % to about 0 . 3 % , in another example from 0 . 5 mM erythromycin , 0 . 5 mM saccharin , 3 % propylene about 0 .05 % to about 0 . 2 % , in another example from about 25 glycol, and 2 mM GG was used as the control. 0 .01 % 0 .07 % to about 0 . 15 % , in another example from about polyquaternium - 2 modulated the bitterness in all of the 0 .08 % to about 0. 13 % , and in another example from about compositions, including components that were very bitter, 0 .09 % to about 0 . 11 . In one example , the composition can like 1 , 10 - phenanthroline , saccharin , and propylene glycol. contain about 0 . 1 % polyquaternium - 2 , polyquaternium - 17 , Surprisingly, polyquaternium - 2 completely blocked the bit and / or polyquaternium - 18 . In another example , the compo - 30 terness from saccharin and substantially reduced the bitter sition can contain less than about 1 % polyquaternium - 2 , ness of both propylene glycol and 1 , 10 - phenanthroline . polyquaternium - 17 , and /or polyquaternium - 18 , in another FIG . 5C compares the modulation of bitterness , if any , of example less than about 0 . 5 % , in another example less than solutions comprising 2 mM of a composition and 0 .01 % about 0 . 3 % , in another example less than about 0 . 2 % , in polyquaternium - 2 in the in vitro Assay for Taste Receptors another example less than about 0 . 15 % , and in another 35 as described hereafter. The compositions tested were example less than about 0 .12 % . amygdalin , benzamide , brucine, e - Caprolactam , N -methyl In one example , polyquaternium - 2 , polyquaternium - 17 , thiourea , orphenadrine hydrochloride, 1 ,10 -phenanthroline , and / or polyquaternium - 18 can be added to the composition . procainamide hydrochloride , and clorhesidice . Polyquater For instance , the composition can contain polyquaternium - nium - 2 significantly reduced the bitterness of benzamide 2 , polyquaternium - 17 , and /or polyquaternium - 18 . In another 40 and brucine and moderately reduced the bitterness of 1 , 10 example , polyquaternium - 2 , polyquaternium - 17 , and / or phenanthroline . However, polyquaternium - 2 did not signifi polyquaternium - 18 can be administered simultaneously with cantly reduce the bitterness of orphenadrine hydrochloride , the composition . In another example , polyquaternium - 2 , which is the most bitter component in FIG . 5C . Polyquater polyquaternium - 17 , and /or polyquaternium - 18 can be nium - 2 may also modulate the bitterness of compositions administered before the composition . In one example the 45 that are only slightly bitter such as amygdalin , e - Capro polyquaternium - 2 , polyquaternium - 17 , and / or polyquater - lactam , N -methylthiourea , procainamide hydrochloride , and nium - 18 can be administered immediately before the com - chlorhesidice . position and in one example the polyquaternium - 2 , poly - FIG . 6 compares ten full formulations diluted to 0 .617 % quaternium - 17 , and /or polyquaternium - 18 can be with the same ten formulations diluted to 0 .617 % with administered and then a period of time can pass before 50 0 .02 % polyquaternium - 2 the in vitro Assay for Taste Recep consuming the composition . tors as described hereafter. The formulations are described in FIG . 5A compares the modulation of bitterness , if any, of Table 1 below . FIG . 6 also includes a formulation with 2 mM solutions comprising 0 .2 mM composition and 0 .02 % poly GG and 10 uM Ionomycin , calcium salt, which were both quaternium - 2 in the in vitro Assay for Taste Receptors as used as controls . TABLE 1
Dose Formulation Size Active Ingredients per Dose Excipients Hyland 's ® 15 mL Allium cepa 6X , Hepar Citric acid , glycyrrhiza DEFEND Cold & sulfuris calcareum 12X , extract , purified water, Cough Hydrastis canadensis 6X , sodium benzoate N . F ., ( Lot # 114220 ) Natrum Muriaticum 6X , vegetable glycerine. Phosphorus 12X , Pulsatilla 6X , Sulphur 12X US 9 ,827 ,320 B2
TABLE 1 -continued Dose Formulation Size Active Ingredients per Dose Excipients PediaCare ® 5 ml Phenylephrine HCl (2 . 5 mg ) Carboxymethylcellulose Decongestant sodium , citric acid , edetate ( Lot # 18263 ) disodium , FD & C red # 40 , flavors , glycerin , sodium benzoate , sodium citrate , sorbitol, sucralose , water Chestal ® Honey 2 US tsp Antimonium tartaricum 6C , Citric acid , honey, purified ( Lot # M0092897 ) ( 9 . 9 mL) Bryonia 3C , Coccus cacti 3C , water, sodium benzoate , Drosera 3C , Ipecacuanha 3C , sucrose Pulsatilla 6C , Rumex crispus 6C , Spongia tosta 3C , Sticta pulmonaria 3C Nature ' s Way® , 7 . 5 mL Pelargonium sidoides IX Alcohol ( 8 . 2 % ), fructose , Umcka ® natural menthol, natural ColdCare , Mint spearmint flavor , purified Menthol Flavor water, vegetable - source ( Lot # 125637 ) glycerin Nighttime Cold & 30 mL AcetaminophenAcetam (650 mg) , and Citric Acid , sodium citrate Flu Relief similar Dextromethorphan HBr ( 30 mg ) dihydrate , FD & C Blue # 1 , to Nyquil ® Red # 40 , purified water , without saccharin , ace sulfame Doxylamine potassium , sodium , propylene glycol, alcohol, PEG - 8 , high fructose corn syrup , flavor Nighttime Cold & 30 ml Acetaminophen (650 mg ) , and Citric Acid , sodium citrate Flu Relief similar Dextromethorphan HBr ( 30 mg) dihydrate , FD & C Blue # 1 , to NyQuil ® cherry Red # 40 , purified water, flavor without saccharin , ace sulfame Doxylamine potassium , sodium , propylene glycol, alcohol , PEG - 8 , high fructose corn syrup , flavor Nighttime Cold & 30 mL Acetaminophen (650 mg) , and Citric Acid , sodium citrate Flu Relief similar Dextromethorphan HBr ( 30 mg ) dihydrate , Red # 40 , flavor, to Alcohol- Free purified water , saccharin , ace NyQuil ® without sulfame potassium , sodium , Chlorpheniramine propylene glycol, sodium benzoate , Carboxymethylcellulose sodium , PEG - 8 , high fructose corn syrup DayQuil ® Cold & 30 mL Acetaminophen (325 mg) , Citric Acid , FD & C Yellow Flu Relief Dextromethorphan FIBr ( 10 mg) , No. 6 , flavor, glycerin , (Lot # and Phenylephrine HCI propylene glycol, purified 124917193U ) (5 mg ) water , saccharin sodium , sodium benzoate , sodium chloride, sodium citrate , sorbitol, sucralose , xantham gum DayQuil ® Severe 30 mL Acetaminophen (650 mg) , Citric Acid , FD & C Yellow Guaifenesin ( 400 mg) , No. 6 , flavor, glycerin , Dextromethorphan HBr ( 20 mg) , propylene glycol, purified and Phenylephrine HCl water, saccharin sodium , ( 10 mg) sodium benzoate , sodium chloride , sodium citrate , sorbitol, sucralose , xantham gum Mucinex ® Fast 20 mL Dextromethorphan HBr (20 mg) Anhydrous citric acid , Max ® DM Max Guaifenesin ( 400 mg) dextrose , ( Lot # 1002471 ) D & C Red # 33, FD & C Red # 40 , flavors , glycerin , methylparaben , potassium sorbate , propylene glycol, propylparaben , purified water , saccharin sodium , sodium hydroxide , sucralose , xanthan gum 60 In the assays of FIG . 6 , 0 .02 % polyquaternium - 2 was flavor without doxylamine, the Nighttime Cold & Flu Relief effective in substantially reducing or completely reducing similar to Alcohol - Free NyQuil® without chlorpheniramine , the bitterness in all of the full formulations . Polyquater - and DayQuil® . The 0 . 02 % polyquaternium - 2 significantly nium - 2 completely or almost completely reduced the bitter reduced the bitterness of DayQuil® Severe and Mucinex® from Nature ' s Way® UmckaTM ColdCare , the Nighttime 65 Fast- Max® DM Max . Cold & Flu Relief similar to Nyquil® without doxylamine , FIG . 7 compares the bitterness , as determined by the DPP the Nighttime Cold & Flu Relief similar to Nyquil® cherry panel, of the examples described in Table 2 below . The high US 9 ,827 ,320 B2 12 fructose corn syrup (HFCS ) base contains 46 .7 % HFCS identical composition without polyquaternium - 2 , poly stock , 5 . 9 % PEG - 400 ( polyethylene glycol 400 ) , 8 .6 % pro quaternium - 17 , and/ or polyquaternium - 18 , in another pylene glycol, 7 . 4 % ethanol, and 30 .07 % water . Excipients , example by at least about 4 % , in another example by at least including propylene glycol, can be bitter and the polyquater about 10 % , in another example the DPP after expectoration nium - 2 can block the bitterness of the excipients in the 5 bitterness by at least about 15 % , in another example by at HFCS base . least about 18 % , in another example by at least about 20 % , and in another example by at least about 22 % . Polyquaternium - 2 , polyquaternium - 17 , and /or poly TABLE 2 quaternium - 18 can be added to compositions , in particular Example High Fructose Corn Syrup Base Polyquaternium - 2 10 liquid pharmaceutical compositions . In one example , the q . s . 0 % composition contains from about 0 .01 % to about 1 % poly q . s . 1 % quaternium - 2 , polyquaternium - 17 , and/ or polyquaternium q . s . 0 . 3 % 18 , in another example from about 0 .03 % to about 0 . 3 % , in q . s . 0 . 1 % another example from about 0 .05 % to about 0 . 2 % , in q . s . 0 .03 % 15 another example from about 0 .07 % to about 0 .15 % , in q . s . 0 .01 % another example from about 0 . 08 % to about 0 . 13 % , and in another example from about 0 .09 % to about 0 . 11. In one Each panelist sampled 10 mL of each example using a example , the composition can contain about 0 . 1 % poly " swish -and -spit ” approach and rated the formulation for quaternium - 2 , polyquaternium - 17 , and /or polyquaternium perceived bitter intensity . The DPP panel includes panelists 2018 . In another example, the composition can contain less that are trained and validated in SpectrumTM Descriptive than about 1 % polyquaternium - 2 , polyquaternium - 17 , and / Analysis methodology and evaluate bitterness on a 60 point or polyquaternium - 18 , in another example less than about scale . 0 . 5 % , in another example less than about 0 . 3 % , in another It was surprisingly found that the Example 4 , which example less than about 0 . 2 % , in another example less than contained 0 . 1 % polyquaternium - 2 was less bitter than 25 about 0 . 15 % , and in another example less than about 0 . 12 % . Examples 2 and 3 , which had higher levels of Polyquater In one example , the polyquaternium - 2 , polyquaternium nium - 2 . Examples 5 and 6 were also less bitter than 17 , and /or polyquaternium - 18 can be used in combination Examples 2 and 3 and may still be acceptable to consumers. with a bitter food or beverage . Non -limiting examples of FIG . 8 compares the bitterness , as determined by the DPP bitter foods can include artichokes, arugula ( Eruca sativa ) , panel , of the following examples: 30 asparagus, basil including , but not limited to , holy basil , Example 7 was commercially available DayQuil® Severe bitter melon , broccoli , Brazil nuts , Brussels sprouts , burdock (Lot # 3308171931 , expiration date October 2015 ) root, cabbage , castor oil, chard , cauliflower , chayotes, which contains four actives : APAP (216 . 67 mg per 10 chicory , chocolate including, but not limited to , dark choco mL ) , GG ( 133 .33 mg per 10 mL ) , phenylephrine HC1 late and unsweetened cocoa , citrus fruits and juices from (PE ) ( 3 . 33 mg per 10 mL ) , and dextromethorphan 35 citrus fruits including, but not limited to lemons , limes and (DXM ) (6 .67 mg per 10 mL ). DayQuil® Severe also grapefruit, citrus peels , cloves, collard greens, cress , cucum contains the following excipients : citric acid , FD & C bers , cumin , dandelion greens , dill , eggplant, endive , fenu Yellow No . 6 , flavor, glycerin , propylene glycol, puri greek , ginger , guarana , Jerusalem artichoke , hazelnut , kale , fied water , saccharin sodium , sodium benzoate , sodium lemon balm , lettuce , maca , melons , milk thistle including chloride , sodium citrate , sorbitol , sucralose , Xanthan 40 the leaves , mushrooms, mustard , neem leaves , nettles , olives gum including , but not limited to , uncured olives , oregano , pak Example 8 was the DayQuil® Severe of Example 7 with choi, pumpkin , radicchio , radishes , rapini, rhubarb including the addition of 0 . 1 % polyquaternium - 2 . the leaves , rosemary , rose root (Rhondiola rosea ) , rutabaga , The DPP panel for FIG . 8 was conducted according to the saffron , sauerkraut , sesame seeds , sesame oil , squash includ procedure described herein for FIG . 7 . Polyquaternium - 2 45 ing but not limited to Zucchini and other summer squash , reduced the overall bitterness in mouth , after expectoration , thistles, tomatoes , turmeric , and combinations thereof. and at three minutes . The in mouth bitter was reduced by Non - limiting examples of beverages can include coffee , about 50 % and the after expectoration bitter was reduced by teas including , but not limited to , green tea , white tea , and over 10 % . The three minute bitter was only reduced slightly black tea , tonic water, South American mate , and alcoholic and there was not a noticeable difference in bitterness after 50 beverages including , but not limited to beer, wine , and ten minutes. However, it can be most important to reduce the spirits , and combinations thereof. bitterness when the composition is in the mouth and imme- There are many compounds that can make foods and diately after it has been expectorated because this is the time beverages bitter. For instance , two components that can when the composition is most bitter and unpleasant to the make beer bitter can be hops and ethanol. Polyquaternium - 2 , consumer. 55 polyquaternium - 17 , and / or polyquaternium - 18 can modu In one example , the DPP in mouth bitter is reduced by at late the bitterness of one or more bitter compounds. In one least about 5 % as compared to the in mouth bitterness of an example , polyquaternium - 2 can block specific bitter com identical composition without polyquaternium - 2 , poly - pounds . quaternium - 17 , and / or polyquaternium - 18 , in another In one example , the food and /or beverage compositions example by at least about 10 % , in another example by at 60 can be consumed as whole foods and beverages . In another least about 15 % , in another example by at least about 20 % , example , the food and / or beverage compositions can be in another example by at least about 25 % , in another partially consumed and can be extracted or condensed or example by at least about 35 % , in another example by at otherwise changed before consumption . In another example , least about 40 % , in another example by at least about 45 % , the food and /or beverage compositions can be made into and in another example by at least about 50 % . In one 65 dosage forms, for instance to provide a supplement. example , the DPP after expectoration bitter is reduced by at In one example, polyquaternium - 2 , polyquaternium - 17 , least about 4 % as compared to the in mouth bitterness of an and /or polyquaternium - 18 can be added to a composition US 9 ,827 ,320 B2 13 14 intended for use by children . Children can be especially to about 15 % glycerin , in another example from about 5 % sensitive to bitter tastes and adding polyquaternium - 2 , poly - to about 10 % glycerin , and in another example from about quaternium - 17 , and / or polyquaternium - 18 can make bitter 7 % to about 9 % glycerin . compositions, for instance foods, beverages , supplements Non - limiting examples of synthetic sweeteners can and medicines more palatable to children . 5 include sodium saccharin , acesulfame potassium , sucralose , In one example , the composition can include a variety of aspartame, monoammonium glycyrrhizinate , neohesperidin orally administered dosage forms, which can contain drug dihydrochalcone , thaumatin , neotame, cyclamates, and mix actives . Non -limiting examples of dosage forms can include tures thereof. In one example the composition can comprise a liquid medication , particles suspended in a liquid formu - from about 0 . 01 % to about 0 . 5 % artificial sweetener, in lation , a solid in a gelatin or foam , or a solid dose in the form 10 another example from about 0 . 1 % to about 0 . 3 % artificial of a tablet , powder, granules, pellets , microspheres, nano sweetener , and in another example about 0 . 15 % to about spheres , beads, or nonpareils , and combinations thereof. In 0 .25 % artificial sweetener . one example , the dosage form is a liquid medication . Dosage Non - limiting examples of high intensity natural sweeten forms can be orally administered and can be swallowed ers can include neohesperidin dihydrochalcone , stevioside , immediately, slowly dissolved in the mouth , or chewed . 15 rebaudioside A , rebaudioside C , dulcoside, monoammonium Non -limiting examples of additional solvents can include glycrrhizinate , thaumatin , and combinations thereof. water , ethanol, glycerol, propylene glycol, polyethylene The liquid composition can optionally include one or glycol 400 , polyethylene glycol 200 , and mixtures thereof. more sensates . Non - limiting examples of sensates can In one example the medication comprises from about 40 % include cooling sensates, warming sensates, tingling sen to about 95 % solvent , in another example from about 50 % 20 sates , and combinations thereof. Sensates can useful to to about 80 % solvent , and in another example from about deliver signals to the user . 55 % to about 60 % solvent, and in another example from In one example the sweetener can be Rebiana® , a ste about 68 % solvent to about 72 % solvent . violglycoside, commercially available from Cargill® Corp ., In one example , the medication can contain water and Minneapolis , Minn . , which is an extract from the leaves of propylene glycol. In one example , the medication comprises 25 the Stevia rebaudiana plant ( hereinafter referred to as “ Rebi from about 15 % to about 80 % water, in another example ana " ) . This is a crystalline diterpene glycoside, about 300x from about 25 % to about 75 % water, in another example sweeter than sucrose . Examples of suitable stevioglycosides from about 40 % to about 70 % water , in another example which may be combined include rebaudioside A , rebaudio from about 35 % to about 45 % water , and in another example side B , rebaudioside C , rebaudioside D , rebaudioside E , from about 57 % to about 66 % water . In another example , the 30 rebaudioside F , dulcoside A , dulcoside B , rubusoside , ste medication can comprise from about 1 % to about 10 % vioside , or steviolbioside . According to particularly desir propylene glycol, in another example from about 2 % to able examples of the present invention , the combination of about 8 % propylene glycol, and in another example from high - potency sweeteners comprises rebaudioside A in com about 3 % to about 6 % propylene glycol. In another example , bination with rebaudioside B , rebaudioside C , rebaudioside the medication can contain from about 5 % to about 40 % 35 F , rebaudioside F , stevioside , steviolbioside , dulcoside A . propylene glycol, in another example from about 15 % to Non - limiting examples of cooling sensates can include about 35 % propylene glycol, and in another example from WS- 23 ( 2 - Isopropyl- N , 2 , 3 - trimethylbutyramide ), WS- 3 about 20 % to about 30 % propylene glycol. In another ( N - Ethyl- p -menthane - 3 - carboxamide ), WS - 30 ( 1 - glyceryl example , the medication can comprise from about 1 % top -mentane - 3 -carboxylate ) , WS - 4 ( ethyleneglycol- p -meth about 15 % ethanol, in another example from about 3 % to 40 ane - 3 - carboxylate ), WS - 14 ( N - t -butyl - p -menthane - 3 - car about 12 % ethanol, and in another example from about 6 % boxamide ), WS - 12 ( N - ( 4 - ,ethoxyphenyl ) - p -menthane - 3 to about 10 % ethanol. carboxamide) , WS - 5 ( Ethyl- 3 - (p -menthane - 3 - carboxamido ) The compositions can comprise a sweetener to provide acetate , Menthone glycerol ketal (sold as Frescolat® MGA sweetness and taste masking of the actives and excipients by Haarmann & Reimer) , ( - ) -Menthyl lactate ( sold as that provide a bitter character . In one example , the compo - 45 Frescolat® ML by Haarmann & Reimer ) , ( - ) -Menthoxy sition comprises from about 2 % to 25 % sweetener , in propane - 1 , 2 - diol ( sold as Coolant Agent 10 by Takasago another example from about 5 % to 20 % sweetener, in International) , 3 - ( 1 -menthoxy ) propane - 1 , 2 -diol , 3 - ( 1 -Men another example from about 7 % to 15 % sweetener, and in thoxy ) - 2 - methylpropane - 1 , 2 - diol, ( - ) - Isopulegol is sold another example from about 8 % to 12 % sweetener . Non - under the name " Coolact P® " by Takasago International. , limiting examples of sweeteners can include nutritive sweet- 50 cis & trans p -Menthane - 3 , 8 - diols (PMD38 ) - Takasago eners , sugar alcohols , synthetic sugars, high intensity natural International, Questice® (menthyl pyrrolidone carboxylate ) , sweeteners , and combinations thereof. Non - limiting (1R , 3R ,4S ) - 3 -menthyl - 3 , 6 -dioxaheptanoate — Firmenich , examples of nutritive sweeteners can include fructose , (1R ,28 ,5R ) - 3 -menthyl methoxyacetate — Firmenich , (1R , galactose , and combinations thereof. In one example , the 2S ,5R ) - 3 - menthyl 3 , 6 , 9 - trioxadecanoate — Firmenich , ( 1R , sweetener can be high fructose corn syrup . 55 25 ,5R )- menthyl 11 -hydroxy - 3 , 6 , 9 - trioxaundecanoateFir Non - limiting examples of sugar alcohols can include menich , (1R ,28 ,5R )- 3 -menthyl ( 2 -hydroxyethoxy ) acetate — xylitol, sorbitol, mannitol, maltitol, lactitol, isomalt , erthri - Firmenich , Cubebol — Firmenich , Icilin also known as tol, glycerin , and combinations thereof. In one example the AG -3 - 5 , chemical name 1- [2 -hydroxyphenyl ] -4 - [ 2 -nitrop composition can comprise from about 1 % to about 30 % henyl- 1 - 1 , 2 , 3 , 6 - tetrahydropyrimidine - 2 -one ), 4 -methyl - 3 sugar alcohol, in another example from about 5 % to about 60 ( 1 - pyrrolidinyl) - 2 [ 51 ] - furanone , Frescolat ML - menthyl 28 % sugar alcohol, in another example about 10 % to about lactate , Frescolat MGA — menthone glycerin acetal, Pepper 25 % sugar alcohol, and in another example about 15 % to mint oil, L -Monomenthyl succinate , L -monomenthyl glut about 23 % sugar alcohol. In one example the composition arate , 3 - 1 -menthoxypropane - 1, 2 -diol — (Coolact 10 ), 2 - 1 comprises from about 5 % to about 20 % sorbitol, in another menthoxyethanol (Cooltact 5 ) , TK10 Coolact ( 3 - 1 example from about 7 % to about 18 % sorbitol, and in 65 Menthoxy propane - 1 , 2 -diol ) , EvercoolTM 180 ( N - ( 4 another example from about 10 % to about 15 % sorbitol. In cyanomethylphenyl) - p -menthanecarboxamide ) ) , and another example , the composition comprises from about 3 % combinations thereof. In one example , the composition can US 9 ,827 ,320 B2 15 16 comprise from about 0 .005 % to about 1 % cooling sensate , wherein R ¡ represents C1 -C2 n -alkyl ; R2 is 2 -methyl - 1 in another example from about 0 .05 % to about 0 . 5 % cooling propyl and R , is hydrogen , or R , and R , taken together is a sensate, and in another example from about 0 .01 % to about moiety (designated by the dashed lines) having the formula 0 . 25 % cooling sensate . In one example , the cooling sensate can be EverCoolTM 5 ( CH2) n - wherein n is 4 or 5, and combinations thereof. 180 available from Givaudan of Cincinnati , Ohio , as a 5 %¿ 5 In an embodiment, the salivating agent comprises a mate solution of N - ( 4 -cyanomethylphenyl ) - p -menthanecarbox rial wherein R , is 2 -methyl - 1 -propyl and R3 is hydrogen , in amide in a flavoring ingredient cool white grape, or as a another embodiment the salivating agent comprises a mate 7 . 5 % solution of N - ( 4 - cyanomethylphenyl) - p -menthanecar rial wherein R , is C1 n - alkyl, R2 is 2 -methyl - 1 - propyl and boxamide in a flavor ingredient such as spearmint or pep Rz is hydrogen . In another embodiment, the salivating agent permint. 10 comprises trans -pellitorin , a chemical having a structure Non - limiting examples of warming sensates can include according to formula ( II ) : TK 1000 , TK 1 MM , Heatenol - Sensient Flavors , Opta heat - Symrise Flavors , Cinnamon , Capsicum , Capsaicin , Curry , FSI Flavors , Isobutavan , Nonivamide 60162807 , Hotact VEE , Hotact 1MM , piperine , optaheat 295 832 , 15 optaheat 204 656 , optaheat 200 349 , and combinations thereof. Warming sensates can be present from about 0 . 005 % to about 2 % , in another example from about 0 .01 % to about 1 % , and in another example from about 0 . 1 % to about 0 . 5 % . Non - limiting examples of tingling sensates can include In another embodiment, the salivation agent can include sichuan pepper, hydroxy alpha sanshool, jambu extracts , sodium bicarbonate , sodium chloride , trans- pellitorin , and spilanthol, and combinations thereof. In one example , tin - combinations thereof. In one example, salivation agents can gling sensates can be present from about 0 .005 % to about be present from about 0 .05 % to about 2 % , in another 1 % , in another example from about 0 .01 % to about 0 .5 % , 25 embodiment from about 0 . 1 % to about 1 % , and in another and another example from about 0 .015 % to about 0 . 3 % . The composition can comprise a flavoring ingredient. example from about 0 .25 % % to about 0 .75 % . When present, flavoring ingredients are generally used in the The liquid composition can be any color. Non - limiting compositions at levels of from about 0 . 001 % to about 8 % , examples of colors can include red , green , amber, orange , by weight of the composition . yellow , blue , pink , violet, turquoise , and combinations Additional non - limiting examples of flavoring ingredientsnta 30» thereof. In one example , the composition is green . In another can include peppermint oil , corn mint oil , spearmint oil , oil example, the liquid composition is clear. of wintergreen , clove bud oil , cassia , sage, parsley oil, The composition can also comprise a dye that provides marjoram , lemon , lime, orange , mango , cis -jasmone , 2 , 5 the color . Non - limiting examples dyes that may be used in dimethyl -4 -hydroxy -3 ( 2H )- furanone , 5 - ethyl- 3 -hydroxy - 4 the present invention include FD & C blue # 1 , FD & C blue methyl- 2 ( 5H ) - furanone . vanillin , ethyl vanillin . propenyl 35 # 2 , D & C blue # 4 , D & C blue # 9 , FD & C green # 3 , D & C guaethol, heliotropine , 4 - cis -heptenal , diacetyl, methyl -p - green # 5 , D & C green # 6 , D & C green # 8 , D & C orange # 4 , tert- butyl phenyl acetate , menthol, methyl salicylate , ethyl D & C orange # 5 , D & C orange # 10 , D & C orange # 11 , FD & C salicylate , 1 -menthyl acetate , oxanone , alpha - irisone , red # 3 , FD & C red # 4 , D & C red # 6 , D & C red # 7 , D & C red methyl cinnamate , ethyl cinnamate , butyl cinnamate , ethyl # 17 , D & C red # 21, D & C red # 22 , D & C red # 27 , D & C red butyrate , ethyl acetate , methyl anthranilate , iso - amyl 40 # 28 , D & C red # 30 , D & C red # 31 , D & C red # 33 , D & C red acetate , iso - amyl butyrate , allyl caproate , eugenol, eucalyp # 34 , D & C red # 36 , D & C red # 39, FD & C red # 40 , D & C tol, thymol, cinnamic alcohol, octanol, octanal, decanol, violet # 2 , FD & C yellow # 5 , FD & C yellow # 6 , D & C yellow decanal , phenylethyl alcohol, benzyl alcohol, alpha - terpin # 7 , Ext. D & C yellow # 7 , D & C yellow # 8 , D & C yellow # 10 , eol, linalool, limonene , citral, maltol, ethyl maltol, carvone , D & C yellow # 11 , and combinations thereof. In one menthone , B -damascenone , ionone , gamma decalactone , 45 example , the composition comprises from about 0 .001 % to gamma nonalactone, gamma undecalactone and mixtures about 0 . 1 % dye , in another example from about 0 . 002 % to thereof. Generally suitable flavoring ingredients are those containing structural features and functional groups that are about 0 . 05 % dye , and in another example form about less prone to redox reactions . These include derivatives of 0 .003 % to about 0 .01 % dye . flavouring ingredients that are saturated or contain stable In one example , the composition comprises a buffer. The aromatic rings or ester groups. In one example , the compo 50 buffer can help maintain a constant pH within the liquid sition comprises from about 0 .01 % to about 1 % flavoring composition . In one example the liquid composition com ingredients , in another example from about 0 .05 % to about prises from about 0 . 05 % to about 2 % buffer , in another 0 . 5 % flavoring ingredients , and in another example from example from about 0 . 1 % to about 1 % buffer, in another example from about 0 . 15 % to about 0 . 5 % buffer , and in about 0 . 1 % to about 0 . 3 % flavoring ingredients . re 55 another example from about 0 . 18 % to about 0 .25 % buffer. The composition can optionally include one or more » Buffers can include acetate buffers , citrate buffers, and salivation agents . Non - limiting examples of salivation phosphate buffers . Non - limiting examples of buffers can agents include formula ( I ) : include acetic acid , sodium acetate , citric acid , sodium citrate , monobasic sodium phosphate , dibasic sodium phos 60 phate , sodium carbonate , sodium bicarbonate , succinic acid , sodium succinate , potassium dihydrogen phosphate , and phosphoric acid . In one example , the composition comprises a preserva VR tive . In one example the liquid composition comprises from 65 about 0 .01 % to about 1 % preservative , in another example from about 0 .05 % to about 0 . 5 % preservative , in another example from about 0 .07 % to about 0 . 3 % preservative , and US 9 ,827 ,320 B2 17 18 in another example from about 0 . 08 % to about 0 .15 % In one example the liquid composition can comprise from preservative . Non - limiting examples of preservatives can about 0 .01 % to about 0 . 1 % antihistamine , in another include benzalkonium chloride , ethylenediaminetetraacetic example from about 0 .02 % to about 0 .07 % antihistamine, acid ( EDTA ) , benzyl alcohol, potassium sorbate , parabens, and in another example from about 0 .03 % to about 0 .05 % benzoic acid , sodium benzoate , and mixtures thereof. 5 antihistamine . In one example , the antihistamine can be In one example , the composition comprises a thickener. In doxylamine succinate and a dose of liquid medication can one example the liquid composition comprises from 0 . 01 % contain 12 . 5 mg doxylamine succinate . In another example , to 3 % thickener, in another example 0 .05 % to 1 . 5 % thick - the antihistamine can be chlorpheniramine . In one example ener, in another example 0 . 1 % to 0 .75 % thickener, and in a dose can contain 2 mg of chlorpheniramine and in another another example 0 . 12 % to 0 . 3 % thickener . Non - limiting 10 example a dose can contain 4 mg of chlorpheniramine . In examples of thickeners can include xanthan gum , carra another example , the antihistamine can be PE . In one geenan , polyacrylic acid , polyvinylpyrrolidone , cellulosic example a dose can contain 5 mg PE , in another example 10 polymers including carboxymethycellulose , hydroxethylcel - mg PE , and in another example 20 mg PE . In another lulose , hydroxymethylcellulose , and hydroxypropylmethyl- example , the antihistamine can be PSE . In one example a cellulose , and combinations thereof. 15 dose can contain 120 mg PSE and in another example 30 mg In certain examples , the compositions can contain one or PSE . more drug actives. In one example, the composition a liquid Non - limiting examples of antitussives can include DXM , composition containing one or more drug actives. In one codeine, chlophedianol, levodropropizine , and combinations example , the drug actives can be immediate release drug thereof . In one example the liquid medication can comprise actives , extended release drug actives , or delayed release 20 from about 0 .01 % to about 0 . 2 % antitussive , in another drug actives. In one example , the drug active can be for example from about 0 .025 % to about 0 . 1 % , and in another mulated as particles and in another example the active can example from about 0 .04 % to about 0 .075 % antitussive . In be formulated as coated beads. one example the antitussive can be selected from the group In one example , the drug active is a multi - symptom relief consisting of DXM , chlophedianol, and combinations (MSR ) cold / flu active which can be used to treat one or more 25 thereof . In one example a dose can comprise 15 mg DXM , cold / flu symptoms. MSR cold / flu actives can be used to treat in another example 20 mg DXM , and in another example 30 a variety of cold / flu symptoms including nasal congestion , mg DXM . In another example a dose can comprise 12 . 5 mg runny nose , sneezing , headache , dry cough , sore throat, chlophedianol. sinus pressure or pain , chest congestion , muscle aches /pains , Non - limiting examples of pain relievers can include wet/ chesty cough , fever, and combinations thereof. MSR 30 APAP, ibuprofen , ketoprofen , diclofenac , naproxen , aspirin , cold / flu actives can include decongestants , expectorants , and combinations thereof. In one example the liquid medi antihistamines, antitussives, pain relievers , and combina - cation can comprise from about 0 . 5 % to about 3 . 5 % pain tions thereof. reliever, in another example from about 1 % to about 3 % pain In one example , MSR cold / flu actives can be formulated reliever, and in another example from about 1 . 5 % to about for daytime use or nighttime use . In one example , the liquid 35 2 % pain reliever. In one example the pain relievers can medication comprises instructions that direct a user to ingest include APAP , ibuprofen , naproxen , or combinations the medication at night before bedtime. thereof. In one example a dose can comprise 325 mg to 500 Non - limiting examples of expectorants can include mg APAP, in another example 200 mg ibuprofen , and in guaifenesin , ambroxol, bromhexine , and combinations another example , 200 mg naproxen . thereof. In one example , the expectorant can be guaifenesin . 40 In one example , the liquid medication can further com In one example a dose can comprise 200 mg of guaifenesin prise a stimulant such as caffeine . and in another example 400 mg of guaifenesin . In one example , the liquid medication can comprise one Non - limiting examples of antihistamines can include or more MSR cold / flu actives , in another example two or chlorpheniramine , desloratadine , levocetirizine , diphenhy - more MSR cold / flu actives , in another example three or dramine , doxylamine succinate , triprolidine , clemastine , 45 more MSR cold / flu actives, and in another example four or pheniramine, brompheniramine , dexbrompheniramine, lor - more MSR cold / flu actives . In one example , the liquid atadine, cetirizine and fexofenadine , amlexanox , alkylamine medication can comprise exactly one MSR cold / flu active , derivatives, cromolyn , acrivastine, ibudilast, bamipine , in another example exactly two MSR cold / flu actives , in ketotifen , nedocromil, omalizumab , dimethindene , oxato - another example exactly three MSR cold / flu actives , and in mide , pemirolast, pyrrobutamine , pentigetide , thenaldine , 50 another example exactly four MSR cold / flu actives. In one picumast , tolpropamine , ramatroban , repirinast, suplatast example the liquid medication can comprise APAP, dox tosylate aminoalkylethers, tazanolast, bromodiphenhy - ylamine succinate , DXM , and PE . dramine , tranilast, carbinoxamine , traxanox , chlorphenox - In one example , the active can be a plant- derived mate amine , diphenylpyaline , embramine, p -methyldiphenhy - rials . As used herein , non - limiting examples of plant- derived dramine, moxastine , orphenadrine, phenyltoloxamine , 55 materials can include those used in traditional native Ameri setastine , ethylenediamine derivatives , chloropyramine , can , Chinese , Aryuvedic and Japanese medicine, including chlorothen , methapyrilene , pyrilamine , talastine , thenyl- flowers, leaves , stems and roots of plants as well as extracts diamine , thonzylamine hydrochloride, tripelennamine , pip - and isolated active components from the flower, leaves , erazines , chlorcyclizine, clocinizine , homochlorcyclizine , stems, and roots of plants . Plant and Animal based oils and hydroxyzine, tricyclics , phenothiazines, mequitazine , pro - 60 esters such as Omega - 3 - fatty acids and alkyl esters thereof; methazine , thiazinamium methylsulfate , azatadine , cypro - Vitamins ( including but not limited to provitamin and all heptadine , deptropine , desloratadine, isothipendyl, olopata forms of Vitamins C , D , A , B , E , and combinations thereof) ; dine , rupatadine , antazoline , astemizole , azelastine , Fibers : Non - limiting examples of fibers and analogous car bepotastine, clemizole , ebastine , emedastine , epinastine , bohydrate polymers can include pectins , psyllium , guar levocabastine, mebhydroline, mizolastine , phenindamine, 65 gum , xanthan gum , alginaes , gum arabic , fructo - oligosac terfenadine , tritoqualine , phenylephrine (PE ) , pseudophed - charides , inulin , agar, beta - glucans, chitins , dextrins, lignin , rine (PSE ) and combinations thereof. celluloses , non - starch polysaccharides , carrageenan , US 9 ,827 ,320 B2 19 20 reduced starch , and mixtures and /or combinations thereof; Non - limiting examples of anti- flattulents can include Prebiotics: Non -limiting examples of prebiotics suitable for simethicone, activated charcoal , lactase , alpha - galactosidase use in the compositions and methods can include psyllium , enzymes, and combinations thereof; non - limiting examples fructo - oligosaccharides, inulin , oligofructose , galacto -oli of H2 receptor antagonists can include famotidine , raniti gosaccharides, isomalto -oligosaccharides , xylo -oligosac - 5 dine, ciemtidine, nitazidine , and combinations thereof . charides, soy -oligosaccharides , gluco -oligosaccharides , Non -limiting examples of proton pump inhibitors can mannan -oligosaccharides , arabinogalactan , arabinxylan , include omeprazole , lansoprazole , esomeprazole , pantopra lactosucrose , gluconannan , lactulose , polydextrose , oligo zole , rabeprazole , and combinations thereof. dextran , gentioligosaccharide , pectic oligosaccharide , xan A non - limiting example of an anti - inflammatory gastro to 10 intestinal active can include mesalamine . than gum , gum arabic , hemicellulose , resistant starch and its Non - limiting examples of rafting agents can include alg derivatives , reduced starch , and mixtures and / or combina inates , pectins and polysaccharides . tions thereof. Probiotics : Non - limiting examples of probiotic A metal salt includes zinc salts , stannous salts , potassium bacteria suitable for use herein can include strains of Strep salts , copper salts , alkali metal bicarbonate slats , and com tococcus lactis , Streptococcus cremoris , Streptococcus 15 binations thereof. Metal salts have a wide range of functions diacetylactis , Streptococcus thermophilus, Lactobacillus from antimicrobial agents to sensitivity agents or buffers . bulgaricus, Lactobacillus acidophilus, Lactobacillus helve The compositions of the present invention may contain ticus , Lactobacillus bifidus, Lactobacillus casei, Lactoba - metal salt in an amount from about 0 .05 % to about 11 % , cillus lactis , Lactobacillus plantarum , Lactobacillus rham from about 0 . 5 % to about 7 % , or from about 1 % to about nosus, Lactobacillus delbruekii, Lactobacillus 20 5 % , by total weight of the oral care composition . thermophilus, Lactobacillus fermentii, Lactobacillus sali It is common to have a fluoride compound present in varius, Lactobacillus reuteri, Lactobacillus brevis, Lacto - dentifrices and other oral care compositions in an amount bacillus paracasei, Lactobacillus gasseri, Pediococcus cer sufficient to give a fluoride ion concentration in the compo evisiae , Bifidobacterium longum , Bifidobacterium infantis , sition of from about 0 .0025 % to about 5 . 0 % or from about Bifidobacterium adolescentis , Bifidobacterium bifidum , Bifi- 25 0 .005 % to about 2 .0 % , by weight of the oral care compo dobacterium animalis , Bifidobacterium pseudolongum , Bifi - sition to provide anticaries effectiveness . A wide variety of dobacterium thermophilum , Bifidobacterium lactis , Bifido fluoride ion - yielding materials can be employed as sources bacterium bulgaricus, Bifidobacterium breve , of soluble fluoride in the present invention . Representative Bifidobacterium subtilis , Escherichia coli and strains of the fluoride ion sources include : stannous fluoride , sodium genera including Bacillus , Bacteroides, Enterococcus ( e . g ., 30 fluoride , potassium fluoride , amine fluoride , sodium mono Enterococcus faecium ) and Leuconostoc , and mixtures and fluorophosphate , indium fluoride , amine fluorides such as or combinations thereof. Olaflur , and many others . Examples of suitable fluoride Minerals , metals and / or elements: Non - limiting examples ion - yielding materials are found in U . S . Pat. No . 3 ,535 ,421 of minerals , metals , and elements useful in the systems of to Briner et al. and U . S . Pat. No. 3 ,678 , 154 to Widder et al. the present invention include : zinc , iron , calcium , iodine , 35 Stannous salts include stannous fluoride , stannous chlo copper and selenium . When present, the minerals , metals ride , stannous iodide, stannous chlorofluoride , stannous and / or elements can be on or in a suitable carrier, and actetate , stannous hexafluorozirconate , stannous sulfate , comprise from about 1 % to about 50 % by weight and stannous lactate , stannous tartrate , stannous gluconate , stan alternatively from about 2 % to about 30 % , by weight of the nous citrate , stannous malate , stannous glycinate , stannous composition comprising the mineral, metal or element and 40 pyrophosphate , stannous metaphosphate , stannous oxalate , the carrier. stannous phosphate , stannous carbonate , and combinations In another example , the active can be a gastrointestinal thereof. Dentifrices containing stannous salts , particularly active . Non - limiting examples of gastrointestingal actives stannous fluoride and stannous chloride , are described in can include anti -diarrheal actives , laxatives , anti -nausea and U . S . Pat. No . 5 ,004 ,597 to Majeti et al. Other descriptions of anti -emetic actives, anti - flattulents , proton pump inhibitors , 45 stannous salts are found in U .S . Pat . No . 5 ,578 ,293 issued to anti - inflammatory gastrointestinal actives , rafting agents , Prencipe et al. and in U . S . Pat . No. 5 , 281, 410 issued to and combinations thereof . Lukacovic et al. In addition to the stannous ion source , other Non -limiting examples of anti - diarrheal actives can ingredients used to stabilize the stannous may be included , include loperamide, bismuth - containing compositions , bis such as the ingredients described in Majeti et al. and muth subsalicylate , colloidal bismuth subcitrate , bismuth 50 Prencipe et al . subcitrate , kaolin , pectin , clays such as attapulgite , activated Zinc salts include zinc fluoride, zinc chloride, zinc iodide, charcoal, and combinations thereof. zinc chlorofluoride, zinc actetate , zinc hexafluorozirconate , Non - limiting examples of laxatives can include fiber, zinc sulfate , zinc lactate , zinc tartrate , zinc gluconate , zinc resistant starch , resistant maltodextrin , pectin , cellulose , citrate, zinc malate , zinc glycinate , zinc pyrophosphate , zinc modified cellulose , polycarophil , senna , sennosides, bisa - 55 metaphosphate , zinc oxalate , zinc phosphate , zinc carbon codyl, sodium phosphate , docusate , magnesium citrate , min ate , and combinations thereof. eral oil , glycerin , aloe, castor oil , magnesium hydroxide, and Potassium salts include potassium nitrate, potassium cit combinations thereof. rate , potassium oxalate , potassium bicarbonate , potassium Non - limiting examples of anti -nausea and anti - emetic acetate , potassium chloride, and combinations thereof. actives can bismuth containing compositions including bis - 60 In one example , the copper salt can be selected from muth subsalicylate , phosphated carbohydrates , diphenhy - copper fluoride , copper chloride, copper iodide, copper dramine , cyclizine , meclizine , and combinations thereof; chlorofluoride , copper actetate , copper hexafluorozirconate , non - limiting examples of antacids can include sodium bicar - copper sulfate , copper lactate , copper tartrate , copper glu bonate , sodium carbonate , calcium carbonate , magnesium conate , copper citrate , copper malate , copper glycinate , carbonate , magnesium hydroxide , aluminum hydroxide , 65 copper pyrophosphate , copper metaphosphate , copper magnesium silicates, alginic acids, sodium alginate , oxalate , copper phosphate , copper carbonate, and combina magaldrate , and combinations thereof. tions thereof. In a further example , the copper salt can be US 9 , 827 , 320 B2 22 selected from copper gluconate , copper acetate , copper antimicrobial agents include chlorhexidine , and flavor oils glycinate, and combinations thereof. such as thymol. In another example , the antimicrobial agent Alkali metal bicarbonate salts are soluble in water and can include triclosan . unless stabilized , tend to release carbon dioxide in an The compositions of the present invention may contain aqueous system . Sodium bicarbonate , also known as baking 5 antimicrobial agents in an amount of from about 0 .035 % or soda , can be the preferred alkali metal bicarbonate salt . The more , from about 0 . 1 % to about 1 . 5 % , from about 0 . 045 % alkali metal bicarbonate salt also functions as a buffering to about 1. 0 % , or from about 0 .05 % to about 0 .10 % , by total agent. Because of the pH at which alkali metal bicarbonate weight of the composition . salts buffer, the bicarbonate salt may be in a phase separate Bleaching agents can include peroxides , perborates, per from the stannous ion source . In certain examples , the 10 carbonates, peroxyacids , persulfates, and combinations thereof. Suitable peroxide compounds include hydrogen composition of the present invention may contain from peroxide , urea peroxide, calcium peroxide , sodium perox about 0 .5 % to about 50 % , from about 0 . 5 % to about 30 % , ide , zinc peroxide , or combinations thereof. One example of from about 2 % to about 20 % , or from about 5 % to about a percarbonate is sodium percarbonate . An example of a 18 % of an alkali metal bicarbonate salt, by weight of the persulfate includes oxones. Some bleaching agents provide composition . a burn sensation within a composition , for example perox Some metal salts which may be used in the present ides and percarbonates . invention , such as zinc chloride, zinc citrate , copper glu The compositions of the present invention may contain conate , and zinc gluconate , are also associated with an off bleaching agents in an amount of from about 0 .01 % to about taste described as dirty , dry, earthy ,metallic , sour, bitter, and 20 30 % , from about 0 .1 % to about 10 % , or from about 0 .5 % to astringent. about 5 % , by total weight of the composition . Carrier materials include water , glycerin , sorbitol, poly Surfactants may include anionic surfactants such as ethylene glycols having a molecular weight of less than organophosphate , which include alkyl phosphates . These about 50 ,000 , propylene glycol and other edible polyhydric surface active organophosphate agents have a strong affinity alcohols , ethanol, or combinations thereof. The composi - 25 for enamel surface and have sufficient surface binding tions of the present invention include from about 5 % to propensity to desorb pellicle proteins and remain affixed to about 80 % , by weight of the composition , of a carrier enamel surfaces. Suitable examples of organophosphate material. In certain examples , the compositions contain compounds include mono -, di- or triesters represented by the carrier materials in an amount of from about 10 % to about general structure below wherein Z1, Z2 , or Z3 may be 40 % , by total weight of the composition . 30 identical or different, at least one being an organic moiety , Antimicrobial agents include quaternary ammonium com in one example selected from linear or branched , alkyl or pounds . Those useful in the present invention include, for alkenyl group of from 1 to 22 carbon atoms, optionally example , those in which one or two of the substitutes on the substituted by one or more phosphate groups; alkoxylated quaternary nitrogen has a carbon chain length ( typically , alkyl or alkenyl, ( poly ) saccharide , polyol or polyether alkyl group ) from about 8 to about 20 , typically from about 35 group . 10 to about 18 carbon atoms while the remaining substitutes ( typically alkyl or benzyl group ) have a lower number of carbon atoms, such as from about 1 to about 7 carbon atoms, typically methyl or ethyl groups. Dodecyl trimethyl ammo - 40 2 - 0 _ 0 — 22 nium bromide , tetradecylpyridinium chloride, domiphen ! bromide , N - tetradecyl - 4 - ethyl pyridinium chloride , dodecyl 0 - 23 dimethyl ( 2 -phenoxyethyl ) ammonium bromide , benzyl dimethoylstearyl ammonium chloride, quaternized 5 -amino Some other organophosphate agents include alkyl or 1 , 3 -bis ( 2 - ethyl- hexyl ) - 5 -methyl hexahydropyrimidine, ben - 45 alkenylphosphate esters represented by the following struc zalkonium chloride , benzethonium chloride and methyl ben - ture : zethonium chloride are exemplary of typical quaternary ammonium antibacterial agents . Other quaternary ammonium compounds include the pyridinium compounds . Examples of pyridinium quaternary 50 RifOCnH2n ) a (OCmH2m ); - O - P - 0 - 22 ammonium compounds include bis[ 4 - ( R - amino ) - 1 -pyri =ASC -0 dinium ]alkanes as disclosed in U . S . Pat. No. 4 ,206 ,215 , Jun . -
3 , 1980 , to Bailey and cetylpyridinium and tetradecylpyri N dinium halide salts ( i .e . , chloride , bromide , fluoride and iodide ) . 55 The compositions of the present invention may also wherein R1 represents a linear or branched , alkyl or alkenyl include other antimicrobial agents including non - cationic group of from 6 to 22 carbon atoms, optionally substituted antimicrobial agents such as halogenated diphenyl ethers , by one or more phosphate groups; n and m , are individually phenolic compounds including phenol and its homologs, and separately , 2 to 4 , and a and b , individually and mono and poly -alkyl and aromatic halophenols , resorcinol 60 separately, are 0 to 20 ; Z2 and Z3 may be identical or and its derivatives , xylitol, bisphenolic compounds and different, each represents hydrogen , alkali metal, ammo halogenated salicylanilides , benzoic esters , and halogenated nium , protonated alkyl amine or protonated functional alkyl carbanilides. Also useful antimicrobials are enzymes, amine such as an alkanolamine , or a R1 — (OCnH2n ) a including endoglycosidase , papain , dextranase , mutanase , (OCmH2m ) b - group . Examples of suitable agents include and combinations thereof . Such agents are disclosed in U . S . 65 alkyl and alkyl (poly )alkoxy phosphates such as lauryl Pat. No . 2 , 946 ,725 , Jul . 26 , 1960 , to Norris et al . and in U . S . phosphate ; PPG5 ceteareth - 10 phosphate; Laureth - 1 phos Pat. No. 4 , 051, 234 to Gieske et al. Examples of other phate ; Laureth - 3 phosphate ; Laureth - 9 phosphate ; Trilau US 9 ,827 ,320 B2 23 24 reth - 4 phosphate ; C12 - 18 PEG 9 phosphate ; Sodium dilau - amount. In varying examples , the amount of pyrophosphate reth - 10 phosphate . In one example , the alkyl phosphate is salt may be from about 1 . 5 % to about 15 % , from about 2 % polymeric . Examples of polymeric alkyl phosphates include to about 10 % , or about 3 % to about 8 % , by total weight of those containing repeating alkoxy groups as the polymeric the oral care composition . portion , in particular 3 or more ethoxy, propoxy isopropoxy 5 Abrasive polishing material can be any material that does or butoxy groups . not excessively abrade dentin . The oral care compositions Zwitterionic or amphoteric surfactants useful in the pres - can contain abrasive polishing material in an amount of from ent invention can include derivatives of aliphatic quaternary about 6 % to about 70 % or from about 10 % to about 50 % , by ammonium , phosphonium , and sulfonium compounds, in weight of the oral care composition . Typical abrasive pol which the aliphatic radicals can be straight chain or 10 ishing materials include silicas including gels and precipi branched , and wherein one of the aliphatic substituents tates; aluminas; phosphates including orthophosphates , contains from about 8 to 18 carbon atoms and one contains polymetaphosphates , and pyrophosphates , and mixtures an anionic water - solubilizing group , such as carboxy, sul thereof. Specific examples include dicalcium orthophos fonate , sulfate , phosphate or phosphonate. Suitable ampho phate dihydrate , calcium pyrophosphate , tricalcium phos teric surfactants include betaine surfactants such as dis - 15 phate , calcium polymetaphosphate , insoluble sodium closed in U . S . Pat. No . 5 , 180 ,577 to Polefka et al. Typical polymetaphosphate , rice hull silica , hydrated alumina , beta alkyl dimethyl betaines include decyl betaine or 2 - ( N - decyl- calcium pyrophosphate, calcium carbonate , and resinous N , N - dimethylammonio ) acetate , coco betaine or 2 - ( N - coco - abrasive materials such as particulate condensation products N , N -dimethyl ammonio Jacetate , myristyl betaine , palmityl of urea and formaldehyde , and others such as disclosed by betaine , lauryl betaine , cetyl betaine, stearyl betaine, etc . 20 Cooley et al in U . S . Pat. No. 3 ,070 ,510 . In certain examples, Amphoteric surfactants useful herein further include amine if the oral composition or particular phase comprises a oxide surfactants . The amidobetaines are exemplified by polyphosphate having an average chain length of about 4 or cocoamidoethyl betaine , cocamidopropyl betaine (CAPB ), more , calcium containing abrasives and alumina are not and lauramidopropyl betaine . The unwanted tastes often preferred abrasives . associated with these surfactants are soapy , bitter, chemical, 25 Silica dental abrasives of various types are often used in or artificial. oral care compositions due to their exceptional dental clean Additional suitable polymeric organophosphate agents ing and polishing performance without unduly abrading can include dextran phosphate , polyglucoside phosphate , tooth enamel or dentine . Silica abrasive polishing materials alkyl polyglucoside phosphate , polyglyceryl phosphate , that may be used in the present invention , as well as other alkyl polyglyceryl phosphate, polyether phosphates and 30 abrasives, generally have an average particle size ranging alkoxylated polyol phosphates . Some specific examples are between about 0 . 1 to about 30 um or from about 5 to about PEG phosphate, PPG phosphate, alkyl PPG phosphate, 15 um . The abrasive can be precipitated silica or silica gels PEG /PPG phosphate , alkyl PEG / PPG phosphate , PEG /PPGI such as the silica xerogels described in Pader et al. , U . S . Pat. PEG phosphate , dipropylene glycol phosphate , PEG glyc - No . 3 ,538 , 230 and DiGiulio , U . S . Pat . No. 3 , 862, 307 . Silica eryl phosphate , PBG (polybutylene glycol) phosphate , PEG 35 xerogels marketed under the trade name “ Syloid ” by the cyclodextrin phosphate , PEG sorbitan phosphate , PEG alkyl W . R . Grace & Company , Davison Chemical Division , sorbitan phosphate , and PEG methyl glucoside phosphate . Augusta , Ga .may be used . Also precipitated silica materials Suitable non - polymeric phosphates include alkyl mono such as those marketed by the J . M . Huber Corporation , glyceride phosphate , alkyl sorbitan phosphate , alkylmethyl Edison , N . J . under the trade name, “ Zeodent” , particularly glucoside phosphate , alkyl sucrose phosphates . The impu - 40 the silica carrying the designation “ Zeodent 119 ” , may be rities in these phosphates may induce a burning sensation used . The types of silica dental abrasives useful in the oral Impurities may include dodecanol, dodecanal, benzalde - care compositions of the present invention are described in hyde , and other TRPA1 or TRPV1 agonists . more detail in Wason , U . S . Pat . No . 4 , 340 ,583 ; and Rice Cationic surfactants useful in the present invention can U . S . Pat. Nos . 5 , 589, 160 ; 5 ,603 , 920 ; 5 ,651 , 958 ; 5 ,658 ,553 ; include derivatives of quaternary ammonium compounds 45 and 5 , 716 , 601 . having one long alkyl chain containing from about 8 to 18 Thickening material or binders may be used to provide a carbon atoms such as lauryl trimethylammonium chloride , desirable consistency to the oral care compositions of the cetyl trimethylammonium bromide, coconut alkyltrimethyl- present invention . For example when the oral care compo ammonium nitrite , cetyl pyridinium fluoride , etc . Quater - sitions are in the form of dentifrices, topical oral gels , nary ammonium halides having detergent properties can be 50 mouthrinse , denture product, mouthsprays , lozenges , oral used , such as those described in U .S . Pat. No . 3 , 535 ,421 to tablets or chewing gums, the amount and type of the Briner et al . Certain cationic surfactants can also act as thickening material will depend upon the form of the prod germicides in the compositions disclosed herein . uct. Thickening materials include carboxyvinyl polymers , Anti -tartar agents include pyrophosphate salts as a source carrageenan , hydroxyethyl cellulose, and water soluble salts of pyrophosphate ion . The pyrophosphate salts useful in the 55 of cellulose ethers such as sodium carboxymethylcellulose present compositions include , for example , the mono - , di and sodium hydroxyethyl cellulose . Natural gums such as and tetraalkali metal pyrophosphate salts and combinations gum karaya , xanthan gum , gum arabic , and gum tragacanth thereof. Disodium dihydrogen pyrophosphate can also be used . Colloidal magnesium aluminum silicate or (Na2H2P207 ) , sodium acid pyrophosphate , tetrasodium finely divided silica can be used as part of the thickening pyrophosphate (Na4P207 ) , and tetrapotassium pyrophos - 60 material to further improve texture . Thickening materials phate (K4P207 ) in their unhydrated as well as hydrated can be used in an amount from about 0 . 1 % to about 15 % , by forms are further species. In compositions of the present weight of the oral care composition . invention , the pyrophosphate salt may be present in one of Humectants keep oral care compositions from hardening three ways : predominately dissolved , predominately undis - upon exposure to air and certain humectants can also impart solved , or a combination of dissolved and undissolved 65 desirable sweetness of flavor to dentifrice compositions . pyrophosphate . The amount of pyrophosphate salt useful in Suitable humectants for use in the present invention include making these compositions is any tartar control effective glycerin , sorbitol, polyethylene glycol, propylene glycol, US 9 ,827 ,320 B2 25 26 xylitol, and other edible polyhydric alcohols. The oral care form the working solution and then it is added to the wells compositions of the present invention may comprise humec for an overall reduction of 162 fold . tants in an amount of from about 0 % to about 70 % or from While the specification concludes with the claims par about 15 % to about 55 % , by weight of the oral care ticularly pointing and distinctly claiming the invention , it is composition . 5 believed that embodiments of the present invention will be Assay for Taste Receptors better understood from this description . In all embodiments Human fungiform taste bud cells were isolated from of the present invention , all weight percentages are by tongues of humans as described in Ozdener, Mehmet , and weight of the total composition , unless specifically stated Nancy Rawson . " Primary Culture of Mammalian Taste otherwise . All ratios are weight ratios , unless specifically Epithelium . ” Methods in Molecular Biology ; 2013 ; 945 : 10 stated otherwise . All ranges are inclusive and combinable . 95 - 107 . The number of significant digits conveys neither limitation Then the cells were further cultured according to the on the indicated amounts nor on the accuracy of the mea following procedure. The cells were grown in a Corning® surements . All measurements are understood to be made at cell culture flask , with a surface area of 75 cm ” , a canted 25° C . and at ambient conditions, where “ ambient condi neck , and a 0 . 2 um Vent cap (Catalog # 430641 , available 15 tions” means conditions under about one atmosphere of from VWR International, Bridgeport, N . J ., USA ) at 37° C . pressure and at about 50 % relative humidity . All such using a growth medium containing 500 mL of Iscove' s weights as they pertain to listed ingredients are based on the Modified Dulbecco ' s Media (IMDM ), 100 mL of Ham ' s active level and do not include carriers or by - products that F12 Nutrient Mixture , 60 mL Fetal Bovine Serum ( FBS ) , may be included in commercially available materials , unless and 150 ug /mL Penicillin - Streptomycin cocktail (all growth 20 otherwise specified . media components available from Life Technologies, Grand The dimensions and values disclosed herein are not to be Island , N . Y . , USA ) . understood as being strictly limited to the exact numerical After the cells reach 80 - 90 % confluence, which generally values recited . Instead , unless otherwise specified , each such takes about seven days of cultivation , the cells were released dimension is intended to mean both the recited value and a by adding 3 mL ofGibco® Trypsin - EDTA ( 0 .05 % ) solution 25 functionally equivalent range surrounding that value . For ( available from Life Technologies ) at 37° C . in couple of example , a dimension disclosed as “ 40 mm ” is intended to minutes, followed by adding 12 mL of cell growth medium mean “ about 40 mm . ” to deactivate trypsin . Then the cells were diluted in the Every document cited herein , including any cross refer growth medium at approximately 250 , 000 cells /mL . Next, enced or related patent or application and any patent appli 100 ul volume of cell suspension containing 20 ,000 to 30 cation or patent to which this application claims priority or 30 ,000 cells were seeded into each well of a Falcon 96 benefit thereof, is hereby incorporated herein by reference in Well Black with Clear Flat Bottom TC - Treated Imaging its entirety unless expressly excluded or otherwise limited . Plate (REF # 353219 , available from VWR International, The citation of any document is not an admission that it is Bridgeport, N . J . , USA ) and the cells are grown overnight. prior art with respect to any invention disclosed or claimed After the overnight cultivation , the cell culture media was 35 herein or that it alone , or in any combination with any other removed by aspiration . Then , 100 uL of Calcium -6QF reference or references , teaches , suggests or discloses any solution was added to each well. The Calcium -6QF solution such invention . Further, to the extent that any meaning or was made by dissolving the contents of one vial of Calcium - definition of a term in this document conflicts with any 60F (available from Molecular Devices , Sunnyvale , Calif. , meaning or definition of the same term in a document USA ) in 20 mL of assay buffer , which contains Hank ' s 40 incorporated by reference , the meaning or definition Balanced Salt Solution (HBSS ) with 20 mM HEPES ( 4 - ( 2 - assigned to that term in this document shall govern . hydroxyethyl) - 1 - piperazineethanesulfonic acid ) (both com - While particular embodiments of the present invention ponents are available from Life Technologies) . The plate have been illustrated and described , it would be obvious to was then incubated at 37° C . for 105 min and at room those skilled in the art that various other changes and temperature for 15 min . Then the 96 -well plate is placed in 45 modifications can be made without departing from the spirit a FLIPR® Tetra High Throughput Cellular Screening Sys - and scope of the invention . It is therefore intended to cover tem (available from Molecular Devices ) and 20 uL of in the appended claims all such changes and modifications working solution , as described below , are added to each that are within the scope of this invention . well . The fluorescence signal was read continuously for 5 What is claimed is : min , where the excitation and emission wave lengths used 50 1 . An ingestible composition with reduced bitterness were 488 nM and 510 nM respectively. The peak value comprising from about 0 . 0001 % to about 0 .001 % of a and / or area under the curve after five minutes was calculated polyquaternium selected from the group consisting of poly and recorded . quaternium - 2 , polyquaternium - 17 , polyquaternium - 18 , and In order to form the working solution , the test material combinations thereof , wherein the composition is selected was diluted with the assay buffer. Examples of test materials 55 from the group consisting of bitter foods , bitter beverages , can include , but are not limited to GG solutions, PG solu and combinations thereof, and wherein overall bitterness is tions , 1 , 3 - PPD solutions , full formulations such as those in reduced by at least about 25 % as compared to an identical Example 4 and 5, and combinations thereof. The amount of composition without the polyquaternium , as determined by assay buffer varies depending on the desired final concen - the in vitro Assay for Taste Receptors . tration , which occurs when the test material is in the wells . 60 2 . The ingestible composition of claim 1 wherein an For example , if the test material is GG , it can be desirable overall bitterness is reduced by at least about 40 % as to have a final concentration of 2 mM . Thus , a 12 mM compared to an identical composition without the poly working solution is made and when it is added to the wells , quaternium as determined by the in vitro Assay for Taste the concentration is further reduced to a final concentration Receptors . of 2 mM . In another example , in order to make a working 65 3 . The ingestible composition of claim 1 wherein an solution for Examples 4 and 5 , and other full formulations , overall bitterness is less than about 7000 fluorescence units 1 mL of the example is added to 27 mL of assay buffer to as determined by the in vitro Assay for Taste Receptors . US 9 ,827 ,320 B2 27 28 4 . The ingestible composition of claim 1 wherein an 7 . The ingestible composition of claim 5 wherein an overall bitterness is less than about 5000 fluorescence units overall bitterness is reduced by at least about 40 % as as determined by the in vitro Assay for Taste Receptors . compared to an identical composition without the poly 5 . An ingestible composition with reduced bitterness comprising : quaternium as determined by the in vitro Assay for Taste a . from about 0 .0001 % to about 0 .001 % of a polyquater 5 Receptors . nium selected from the group consisting of polyquater - 8 . The ingestible composition of claim 5 wherein an nium - 2 , polyquaternium - 17 , polyquaternium - 18 , and overall bitterness is less than about 7000 fluorescence units combinations thereof; and as determined by the in vitro Assay for Taste Receptors . b . a bitter component selected from the group consisting 100 of Hops, guaifenesin , phenytoin , omeprazole onsis, cetiriz 10 9 . The ingestible composition of claim 5 wherein an ine , jambu , acetaminophen , methyl formyl anthranilate , overall bitterness is less than about 5000 fluorescence units 2 - aminoacetophenone, beta - terpineol, beta - naphthyl as determined by the in vitro Assay for Taste Receptors. anthranilate , benzoyl anthranilic acid , 1 , 10 -phenan - 10 . The ingestible composition of claim 5 further com throline, saccharin , benzamide , brucine, and combina - prising a sweetener. tions thereof. 6 . The ingestible composition of claim 5 wherein the 11 . The ingestible composition of claim 5 further com composition is selected from the group consisting of bitter prising from about 2 % to about 25 % of a sweetener . foods, bitter beverages, medications , oral care compositions, and combinations thereof. * * * * *