US 20070 197661A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2007/0197661 A1 Bubnis et al. (43) Pub. Date: Aug. 23, 2007

(54) PHENYLEPHRINE LIQUID FORMULATIONS (22) Filed: Feb. 9, 2007 (75) Inventors: William Bubnis, Mechanicsville, Related U.S. Application Data VA (US); Stephanie Shield, (60) Provisional application No. 60/774,634, filed on Feb. Richmond, VA (US); Amanda 21, 2006. Alley, Midlothian, VA (US) Publication Classification Correspondence Address: (51) Int. Cl. WYETH A63L/35 (2006.01) PATENT LAW GROUP 5 GRALDA FARMS (52) U.S. Cl...... 514/646 MADISON, NJ 07940 (57) ABSTRACT An oral, aqueous-based, liquid pharmaceutical composition (73) Assignee: Wyeth, Madison, NJ (US) is provided. The composition comprises up to about 45% w/v glycerin and up to about 10% w/v sorbitol wherein the (21) Appl. No.: 11/704,407 glycerin to sorbitol ratio is about 2:1 to 10:1. US 2007/O 197661 A1 Aug. 23, 2007

PHENYLEPHRINE LIQUID FORMULATIONS the opportunity for phenylephrine degradation. The compo sition of the invention may be a solution or a Suspension. 0010 Preferably the phenylephrine is in a salt form. 0001. This application claims priority from U.S. Provi Suitable salt forms include, but are not limited to, phenyle sional Application file 60/774,634 filed on Feb. 21, 2006 phrine hydrochloride (HCI), hydrobromide (HBr), bitart entitled “Phenylephrine Liquid Formulations, the content arate and tannate salts. Phenylephrine may be used in an of which is incorporated herein in its entirety to the extent amount of about 0.001% w/v to about 10% w/v. Preferably, that it is consistent with this invention and application. phenylephrine is used in an amount of about 0.005% w/v to about 2.5% w/v. Herein % w/v means a percentage deter FIELD OF THE INVENTION mined by the following formula: 0002 An aqueous, oral liquid pharmaceutical composi tion comprising phenylephrine is provided. The composition Weight of component (in grams) (1) is particularly well suited for the relief of cold, cough, flu, wfy 9% = - - - - - X 100 fever, headache, pain, body ache, migraine and allergy Volume of composition (in milliliters symptoms in pediatric patients. Accordingly, for example, 1% w/v/6 phenylephrine means 1 BACKGROUND OF THE INVENTION gram of phenylephrine in 100 ml of the oral liquid compo 0003 Orally administered pharmaceutical compositions sition. are provided to patients in many dosage forms, including 0011. An artificial sweetener is provided to improve Solid forms such as capsules, caplets or tablets and liquid palatability. An artificial sweetener is preferred for use as a forms such as solutions and Suspensions. For many patients Sweetener to the use of conventional Sugar Sweeteners as the including young children, older persons and incapacitated inventors believe, without wishing to be held to the theory, persons, a liquid dose form is preferable because of the ease that conventional Sugars may contribute to the degradation with which it may be swallowed. of phenylephrine in aqueous based compositions. Suitable 0004. Many liquid cough and cold compositions contain artificial Sweeteners, include but are not limited to Sucralose, large amounts of Sorbitol and other Sugars, typically saccharine salts, cyclamates, acesulfame K, dipeptide based included to improve palatability. For example, U.S. Pat. No. Sweeteners, aspartame and mixtures thereof. Sucralose, 5,730,997 discloses a composition containing about 20% to which is a high intensity Sweetener, is particularly well about 45% by weight sorbitol and about 10% to about 15% suited for use in the composition. Sucralose may be used in by weight hydrogenated maltose syrup. Such compositions an amount of about 0.01% w/v to about 0.4% w/v, for are purported to improve palatability but high levels of example. The appropriate amount of artificial Sweetener Sorbitol and maltose may contribute to the degradation of depends on properties and Sweetness intensity of the artifi active ingredients such as phenylephrine, for example. cial Sweetener and target organoleptic properties of the 0005 Accordingly, it would be desirable to have a pal composition. One skilled in the art is familiar with the atable, liquid dosage form comprising phenylephrine with characteristics of Sweeteners and methods for determining reduced propensity for degradation of phenylephrine. amount of sweetener to be used. 0012 Glycerin and sorbitol are used in the composition. SUMMARY OF THE INVENTION In contrast to many conventional commercial cold products, 0006. The pharmaceutical described herein is an aqueous the composition contains more glycerin than Sorbitol. The oral pharmaceutical composition comprising phenylephrine, inventors believe, without wishing to be bound to the theory, artificial Sweetener, up to about 45% w/v glycerin and up to that reduced amounts of sorbitol facilitate stability of the about 10% w/v sorbitol wherein the glycerin to sorbitol ratio phenylephrine and that the glycerol to sorbitol ratio is is about 2:1 to about 10:1. important in achieving a stable, palatable composition. The 0007. The composition may further comprise one or more composition may contain up to 45% w/v glycerin and up to second active agents selected from analgesics, deconges about 10% w/v sorbitol. More preferably the composition tants, expectorants, anti-tussives, antipyretics, anti-inflam may contain about 18% to about 30% w/v glycerin and about matory agents, cough Suppressants and antihistamines. 3% to about 10% w/v sorbitol. Herein the amounts of 0008. The composition may be a solution or a suspen Sorbitol and glycerin are the amounts of standard commer Sion. Suspension embodiments may further comprise vis cial preparations of Sorbitol and glycerin. Commercial Sor cosity modifying agents. bitol (as obtained from SPI Polyols, 321 Cherry Lane New Castle, Del. 19720, or Roquelite Freves 62080 Lestrew, DETAILED DESCRIPTION OF THE France, for example) is an aqueous based composition INVENTION which is 70% sorbitol. Commercial glycerin (as obtained from Dow Chemical Co., 2030 Dow Center, Midland, Mich. 0009. The invention provides an oral, aqueous-based, 48674, or Lyondell, 1221 McKinney St., Houston, Tex. liquid pharmaceutical composition comprising the pharma 77253, for example) is 96% glycerin. One skilled in the art ceutical active phenylephrine. The composition is palatable is familiar with these commercial preparations and methods and has improved phenylephrine Stability. The composition of adjusting amounts should a different glycerin or Sorbitol comprises phenylephrine, an artificial Sweetener, up to about preparation be used. 45% w/v glycerin and up to about 10% w/v sorbitol. The 0013 The composition may contain one or more addi glycerin to sorbitol ratio is about 2:1 to about 10:1. The tional pharmaceutical actives (also referred to as “active(s)'. inventors believe, without wishing to be bound to the theory, “active agent(s)', “therapeutic agent(s)'. “drug(s)). Herein that the glycerin to sorbitol ratio is beneficial to both reference to “first pharmaceutical active” means phenyleph maintaining desirable organoleptic properties and reducing rine and reference to 'second pharmaceutical active' means US 2007/O 197661 A1 Aug. 23, 2007 any active other than phenylephrine. Further, the term sec 0021 Analgesics which may be used in the practice of ond pharmaceutical active may refer to a single species of the invention include but are not limited to aspirin, acetomi active or a plurality of species of actives other than phe nophen, phenacetin and Salicylate salts. nylephrine (e.g., the total number of actives in the compo 0022. Examples of substantially insoluble pharmaceuti sitions may be greater than 2.) For embodiments of the cal actives that may be suspended in the Suspending system composition which are solutions, any additional active of Suspension embodiments include, but are not limited to, should be water soluble. A water-soluble pharmaceutical nabumetone, glimepiride, diclofenac, piroxicam and active means a pharmaceutical active indicated to be soluble meloxican. in water by the Merck Index. Additional actives in suspen 0023. Of the pharmaceutically active compounds described above which may be included in addition to sion embodiments may be water soluble, slightly soluble in phenylepherine in the composition, those which are particu water, or insoluble in an aqueous medium. It should be noted larly preferred are set forth below along with preferred that second pharmaceutical actives are discussed herein in ranges for their inclusion into the claimed pharmaceutical the context of compositions comprising phenylephrine, but composition. aqueous based compositions having the Sorbitol and glycerin 0024 Chlorpheniramine may be used in the pharmaceu ratios discussed herein may be likewise suitable for com tical composition in amounts between about 0.01 w/v and positions comprising one or more of the second active about 0.05 w/v. Preferably chlorpheniramine, when used in agents in the absence of phenylephrine. the pharmaceutical composition, is present in the amount of 0014 Suitable additional or second active agents include about 0.01 w/v to 0.03 w/v. analgesics, decongestants, expectorants, anti-tussives, anti 0025 Brompheniramine maleate may be used in the pyretics, anti-inflammatory agents, cough suppressants and pharmaceutical composition, preferably in the amount of antihistamines. about 0.01 w/v to about 0.03 w/v. 00.15 Antihistamines useful in the practice of the present 0026 Dextromethorphan HBr may be used in the phar invention (along with their preferred salt form) include, but maceutical composition, preferably in the amount of about are not limited to, chlorpheniramine (maleate), bromphe 0.05 w/v to about 0.250 w/v. niramine (maleate); dexchlorpheniramine (maleate), dex 0027 Guaifenesin may be used in the composition in brompheniramine (maleate), triprolidine (HCl), diphenhy amounts of about 0.4% w/v to about 6% w/v and preferably dramine (HCl, citrate), doxylamine (Succinate), in amounts of about 2% w/v to about 4% w/v. tripelenamine (HCl), cyproheptatine (HCl), chlorcyclizine 0028 Acetaminophen may be used in the composition in (HCl), bromodiphenhydramine (HCl), phenindamine (tar amounts of about 0.2% w/v to about 10% w/v and preferably trate), pyrilamine (maleate, tannate), azatadine (maleate); in amounts of about 0.5% w/v to about 3.2% w/v. acrivastine, astemizole, azelastine, cetirizine, ebastine, fex 0029 Chlophendianol may be used in the composition in ofenadine, ketotifen, carbinoxamine (maleate), deslorata amounts of about 0.1% w/v to about 1% w/v and preferably dine, loratadine, pheniramine maleate, thonzylamine (HCl). in amounts of about 0.25% w/v to about 0.5% w/v. mizolastine and terfenadine. 0030) Diphenhydramine may be used in the composition in amounts of about 0.2% w/v to about 2% w/v and 0016. Antitussives useful in the practice of the present preferably in amounts of about 0.5% w/v to about 1% w/v. invention (along with their preferred salt form) include, but 0031 Brompheniramine may be used in the composition are not limited to, chlophendianol, caramiphen (ediylate), in amounts of about 0.016% w/v to about 0.16% w/v and dextromethorphan (HBr), diphenhydramine (citrate, HCl, preferably in amounts of about 0.02% w/v to about 0.08% codeine (phosphate, Sulfate) and hydrocodone. w/v. 0017 Decongestants useful in the practice of the inven 0032 Loratadine may be used in the composition in tion (along with their preferred salt form) include, but are amounts of about 0.02% w/v to about 0.4% w/v and pref not limited to, pseudoephedrine (HCl, sulfate), Ephedrine erably in amounts of about 0.1% w/v to about 0.2% w/v. (HCl, Sulfate), phenylephrine (bitartarate, tannate, HBr, 0033 Aspirin may be used in the composition in amounts HCl), and phenylpropenolamine (HCl). of about 0.8% w/v to about 13% w/v and preferably in 00.18 Expectorants which may be used in the practice of amounts of about 3.2% w/v to about 7.2% w/v. the invention (along with their preferred salt form) include 0034 Doxylamine may be used in the composition in but are not limited to terpin hydrate, guaifenesin (glycerol, amounts of about 0.1% w/v to about 1% w/v and preferably guaiacolate), potassium (iodide, citrate) and potassium gua in amounts about 0.25% w/v to about 0.5% w/v. icolsulfonate. 0035 Amounts of pharmaceutically active compounds 0019 Non-steroidal anti-inflammatory drugs (NSAIDS) incorporated are conventional dosages known to those which may be used in the practice of the invention include, skilled in the art. Further, for pharmaceutical compositions but are not limited to, propionic acid derivatives Such as intended for use in the United States, amounts of pharma ibuprofen, naproxen, ketoprofen, flurbiprofen, fenoprofen, ceutical actives are preferably in compliance with applicable suprofen, fluprofen and fenbufen; acetic acid derivatives FDA regulations regarding dosage of Such compounds. Such as tolmetin Sodium, Zomepirac, Sulindac, and 0036. The pharmaceutically active compounds are pref indomethacin; fenamic acid derivatives Such as mefenamic erably of N.F. (National Formulary) or U.S.P. (United States acid and meclofenamate Sodium; biphenyl carboxylic acid Pharmacopeia) grade. derivatives Such as diflunisal and flufenisal and oxicams 0037 Excipients known by those skilled in the art may be Such as piroXicam, Sudoxicam and isoxicam. useful in the practice of the present invention. Such excipi 0020 Cox 2 inhibitors which may be used in the practice ents may include, but are not limited to, humectants such as of the invention include, but are not limited to, Celecoxib, propylene glycol, defoaming agents, buffers, electrolytes, Rofecoxib and Valdecoxib. preservatives such as sodium benzoate and disodium ede US 2007/O 197661 A1 Aug. 23, 2007 tate, antioxidants, taste masking agents and various flavoring xanthan, hydroxpropylmethylcellulose (HPMC), hydrox and coloring agents, for example. ypropylcellulose (HPC), hydroxyethylcellulose (HEC), gla 0038 Examples of suitable flavoring agents include, but ctomannons such as guar, konjac, locust bean gum and are not limited to, natural and artificial flavors such as mints mamman, for example, microcrystalline cellulose and com (i.e., peppermint, etc.), menthol, chocolate, artificial choco binations thereof. late, bubblegum, both artificial and natural fruit flavors (i.e., 0046 Xanthan gums suitable for use in the present inven cherry, grape, orange, Strawberry, etc.) and combinations of tion are high molecular weight polysaccharides Such as the two or more thereof. It is preferable to avoid flavoring agents Xanthan gum produced by Xanthamonas capestris, for which have aldehyde functional groups (e.g. use non-alde example. Xanthan gum is an article of commerce and is hyde containing flavorants is preferred). Flavoring agents available, for example, from manufacturers such as: Rhodia, are generally provided as a minor component of the com Inc. under the brand name RhodigelTM and from Kelco TM, a position in amounts effective to provide palatable flavor to division of Merck. RhodigelTM 80 Pharm Grade is exem the compositions. Typically, flavoring agents are present in plary of one specific commercial product Suitable for use in amounts in the range of about 0 grams to about 5 grams per the practice of the invention. 100 ml of the composition. 0047 Microcrystalline cellulose is commercially avail 0039 Preservatives useful in the present invention able from suppliers such as FMC (1735 Market Street, include but are not limited to sodium benzoate, sorbates, Philadelphia, Pa. 19103) under the tradename AviceITM Such as potassium Sorbate, salts of edetate (also known as 0048. The amount of viscosity modifier used depends on salts of ethylenediaminetetraacetic acid or EDTA, such as the desired “thickness” of the composition and the type disodium edetate), benzaldionium chloride and parabens viscosity modifier used. Combinations of viscosity modifiers (such as methyl, ethyl, propyl, and butyl p-hydroxybenzoic may be employed. For example, in an exemplary embodi acid esters). Preservatives listed above are exemplary, but ment with a viscosity of about 1500 to about 4500 cps, up each preservative must be evaluated on an experimental to about 1.0 w/v xanthan gum may be used with up to about basis, in each formulation to assure compatibility and effi 3.0 w/v microcrystalline cellulose may be as a viscosity cacy of the preservative. Methods for evaluating the efficacy modifier. of preservatives in pharmaceutical formulations are known 0049. It is preferable to avoid viscosity modifiers with a to those skilled in the art. Sodium benzoate and disodium significant presence of negatively charged moieties or moi edetate are the presently preferred preservative ingredients. eties with propensity to ionize to a negative charge if the 0040 Preservatives are generally present in amounts of structure of the modifier is such that the negatively charged up to one gram per 100 ml of the pharmaceutical composi moiety is readily available for reaction. tion. Preferably the preservatives are present in amounts in 0050. Suspensions are useful for preparing compositions the range of from about 0.01 w/v to about 0.4 w/v of the comprising actives that are Substantially insoluble in water. composition. Typically, the preservative sodium benzoate In Suspension embodiments the phenylephrine is dissolved would be present in the range of about 0.1 w/v to about 0.2 in the aqueous medium. The composition may contain one w/v of the composition, for example. Sodium benzoate was or more second active agents dissolved in the aqueous used in a concentration of about 0.1 W/v in an exemplary medium and/or one or more substantially water insoluble embodiment of the composition. second active agents may be suspended in the composition. 0041) Propylgallate is exemplary of an antioxidant that is For the suspension embodiments, it is preferable that both Suitable for use in the composition. the Suspended Substantially insoluble active ingredients and 0042 Sodium citrate is exemplary of a buffering agent any soluble active ingredients dissolved in the aqueous which may be used in the composition. It is preferable to medium, are distributed to form a Substantially homoge buffer the composition to maintain the pH less than about neous distribution of active ingredients in the pharmaceuti 5.4. More preferably the pH may be maintained in the range cal composition. of about pH 2 to about pH 4.5. 0051 Exemplary pharmaceutical actives that are substan 0043 Coloring agents may also be incorporated in the tially insoluble in the aqueous composition and would be pharmaceutical composition to provide an appealing color to expected to form Suspension include but are not limited to the composition. The coloring agents should be selected to Ibuprofen, Ketoprofen, Naproxen, Celecoxib, Rofecoxib, avoid chemical incompatibilities with other ingredients in Valdecoxib, Nabumetone, Glimepiride, Diclofenac, Piroxi the composition. Suitable coloring agents are well known to cam and Meloxican. For pharmaceutical actives not speci those skilled in the art. fied on this list a pharmaceutical active Substantially 0044. In some embodiments, particularly Suspension insoluble in the aqueous composition means a pharmaceu embodiments, a Surface-modifying agent, such as a surfac tical active designated as relatively insoluble or insoluble in tant, may be used in the pharmaceutical composition to water by the Merck Index. modify the Surface of the Suspended components. Such 0.052 Typically, the composition is provided to a patient surface modification is believed to facilitate diminished in need of treatment in a dosage unit of 5 ml although other irreversible aggregation of the Suspended particles. The dosage units may be likewise Suitable. The dosage unit may Surfactant may be an ionic or non-ionic Surfactant or mix be provided as a single dosage unit or multiples thereof, tures thereof. Exemplary surfactants include but are not based on age, weight and other health parameters deter limited to polysorbates (tweens), SpansTM, togats, lecithin, mined by a physician to be relevant. polyoxyethylene-polyoxypropylene block copolymers and medium chain mono/di-glycerides. EXAMPLE 1. 0045 Typically, suspension embodiments will further 0053 An exemplary composition comprising the single comprise a viscosity modifying agents. Suitable viscosity first pharmaceutical active phenylephrine is provided in modifying agents include but are not limited to chitosan, Table 1. This composition is representative and one of many US 2007/O 197661 A1 Aug. 23, 2007 composition that are within the scope of the invention. The portions of 25% w/v to 40% w/v sorbitol and the composi exemplary embodiment is provided for illustrative purposes. tion of one embodiment of the invention comprising 0.05% W/V phenylephrine in an aqueous based composition using TABLE 1. the proportion of 25% glycerin to 10% sorbitol were pre pared and Subjected to stability testing. The compositions Amount were alike in all other respects except the glycerin to sorbitol Ingredient (grams/100 ml x 100) ratio. Phenylephrine HCl O.05% wiv 0.058 Table 3 shows the results of stability testing over Glycerin (96% USP) 25% wiv Sorbitol (70% Solution USP) 10% Wiv one month at conditions of 60° C. and 60% relative humidity Citric Acid O.75% wiv (herein “60/60"). Table 4 shows the results of stability Micronized Sucralose Powder (NF) 0.2% wiv testing over six months at conditions of 40° C. and 75% menthol 0.02% Wiw relative humidity (herein “40/75'). For both Table 3 and 4, propylene glycol 1.3% ww. colorant 0.01% Wiw stability was assessed as the amount of phenylephrine sodium citrate 0.15% Wiw degradants present as compared to amount of phenylephrine sodium benzoate 0.1% wiv at the indicated time point. At the indicated time points, purified H0 USP Sufficient quantity to samples of the composition were analyzed by HPLC (high make final volume pressure liquid chromatography) and the total peak area attributed to phenylephrine degradants was compared to the 0054 The composition of Table 1 may be prepared by peak area of Phenylephrine. Accordingly, the percentages simple mixing. The ingredients are mixed in a vessel reported in Tables 3 and 5 are percentages based on the total equipped with a mechanical stirrer (e.g., a lightnin mixer), peak area of all phenylephrine degradants to the peak area of the vessel is calibrated and marked to designate the final phenylephrine for the sample analyzed. Volume. An aliquot of water Substantially less than the target final volume is placed in the vessel and the other ingredient TABLE 3 are added sequentially with mixing. Colorants are premixed with a small amount of water prior to addition to the main. Time Phenylephrine Degradants Phenylephrine Degradants Likewise, menthol and propylene glycol, are premixed (months) Gly:Sorb 25:48 Gly:Sorb 25:10 before addition to the main vessel. After all other ingredients O O.O7 O O.25 O.26 O have been added and mixed sufficiently to dissolve, water is 0.5 0.72 O added to bring the total volume of the composition to the 1 1.37 O29 predetermined final Volume and mixing was continued for approximately 10 minutes. EXAMPLE 2 TABLE 4 0055 An exemplary composition comprising phenyleph Time Phenylephrine Degradants Phenylephrine Degradants rine and a second active Brompheniramine maleate is pro (months) Gly:Sorb 25:48 Gly:Sorb 25:10 vided in Table 2. This composition is representative and one O O.O7 O of the many compositions that are within the scope of the 1 O.08 O invention. The exemplary embodiment is provided for illus 2 O16 O 3 O.12 O trative purposes. 6 0.4 O TABLE 2 0059. As Table 3 shows under conditions of 60/60 no Amount phenylephrine degradants were detected in the composition Ingredient (grams/100 ml + 100) of the invention for the first three weeks of the study and Phenylephrine HCl O.05% wiv only 0.29% phenylephrine degradants were detected at the Brompheniramine Maleate 0.02% Wiw end of the fourth week of the study. In contrast phenyleph Glycerin (96% USP) 25% wiv rine degradants were observed at every test point for the Sorbitol (70% Solution USP) 10% wiv Citric Acid O.75% wiv conventional composition with 1.37% phenylephrine Micronized Sucralose 0.2% ww. degradants detected at the end of the fourth week of the Artificial Fruit Flavor 0.2% ww. study. Colorant <0.1% wiv Sodium Citrate 0.10% wiv 0060. As Table 4 shows, under conditions of 40775, no Sodium Benzoate 0.1% ww. phenylephrine degradants were observed over the six-month Purified H-0 Sufficient quantity to make final volume course of the study for the composition of the invention. In contrast phenylephrine degradants were observed at every test point for the conventional composition with 0.4% phe 0056. The composition of Table 2 may be prepared using nylephrine degradants at the end of the sixth month of the the manner of preparation described in Example 1. study. EXAMPLE 3 0061 Although the foregoing invention has been described in some detail by way of illustrations and 0057 Stability data for compositions comprising phe examples for purposes of clarity of understanding. It will be nylephrine are provided in Tables 3 and 4. Compositions obvious that certain changes and modifications may be comprising 0.05% w/v of phenylephrine in an aqueous practiced within the scope of the appended claims. Modifi based composition using the conventional commercial pro cations of the above-described modes of practicing the US 2007/O 197661 A1 Aug. 23, 2007

invention that are obvious to persons of skill in the art are 13. The composition of claim 11, wherein the buffering intended to be included within the scope of the following agent maintains a pH between about 2 and about 4.5 in the claims. composition. 14. The composition of claim 1, further comprising a What is claimed is: preservative. 1. An aqueous oral pharmaceutical composition compris 15. The composition of claim 14, wherein the preservative ing: is selected from the group consisting of Sodium benzoate, a). Phenylephrine; sorbates, parabens, EDTA and combinations thereof. b). artificial sweetener; 16. The composition of claim 1, further comprising an c). up to about 45% w/v glycerin; and antioxidant. d). up to about 10% w/v sorbitol wherein the glycerin to 17. The composition of claim 16, wherein the antioxidant sorbitol ratio is about 2:1 to about 10:1. is propyl gallate. 2. The composition of claim 1, wherein the glycerin to 18. An aqueous pharmaceutical Solution comprising: sorbitol ratio is about 2:1 to about 5:1. a). phenylephrine; 3. The composition of claim 1, wherein the artificial b). artificial sweetener; Sweetener is selected from the group consisting of Sucralose, c). about 18% to about 30% w/v glycerin; and saccharine salts, cyclamates, acesulfame K, dipeptide based d). about 3% to about 10% w/v sorbitol, wherein the Sweeteners, aspartame and mixtures thereof. glycerin to sorbitol ratio is about 2:1 to about 10:1. 4. The composition of claim 3, where in the artificial 19. The solution of claim 18, wherein the glycerin to Sweetener comprises sucralose. sorbitol ratio is about 2:1 to about 5:1. 5. The composition of claim 1, further comprising a flavor 20. The solution of claim 18, wherein the artificial sweet system. ener is selected from the group consisting of Sucralose, 6. The composition of claim 5, wherein the flavor system saccharine salts, cyclamates, acesulfame K, dipeptide based includes non-aldehyde flavorants. Sweeteners, aspartame and mixtures thereof. 7. The composition of claim 1, further comprising at least 21. The solution of claim 20, wherein the artificial sweet one second active agent selected from the group consisting ener comprises sucralose. of analgesics, decongestants, expectorants, anti-tussives, 22. The solution of claim 18, further comprising an antipyretics, anti-inflammatory agents, cough suppressants effective amount of at least one second active agent selected and antihistamines. from the group consisting of analgesics, decongestants, 8. The composition of claim 7, wherein the second active expectorants, anti-tussives, antipyretics, anti-inflammatory agent is selected from the group consisting of non-steroidal agents, cough Suppressants and antihistamines. anti-inflammatory drugs (NSAIDS), propionic acid deriva 23. The solution of claim 22, wherein the second active tives, ibuprofen, naproxen, ketoprofen, flurbiprofen, feno agent is selected from the group consisting of non-steroidal profen, Suprofen, fluprofen, fenbufen, acetic acid deriva anti-inflammatory drugs (NSAIDS), propionic acid deriva tives, tolmetin Sodium, Zomepirac, Sulindac, indomethacin, tives, ibuprofen, naproxen, ketoprofen, flurbiprofen, feno fenamic acid derivatives, mefenamic acid meclofenamate profen, Suprofen, fluprofen, fenbufen, acetic acid deriva sodium, biphenyl carboxylic acid derivatives, diflunisal, tives, tolmetin Sodium, Zomepirac, Sulindac, indomethacin, flufenisal, oxicams, piroXicam, Sudoxicam, isoxicam, chlo fenamic acid derivatives, mefenamic acid meclofenamate rpheniramine, brompheniramine; dexchlorpheniramine, sodium, biphenyl carboxylic acid derivatives, diflunisal, dexbrompheniramine, triprolidine, chlorcyclizine, diphen flufenisal, oxicams, piroXicam, Sudoxicam, isoxicam, chlo hydramine, doxylamine, tripelenamine, cyproheptatine, bro rpheniramine, brompheniramine; dexchlorpheniramine, modiphenhydramine, phenindamine, pyrilamine, azatadine, dexbrompheniramine, triprolidine, chlorcyclizine, diphen acrivastine, astemizole, azelastine, cetirizine, ebastine, fex hydramine, doxylamine, tripelenamine, cyproheptatine, bro ofenadine, ketotifen, carbinoxamine, desloratadine, lorata modiphenhydramine, phenindamine, pyrilamine, azatadine, dine, pheniramine, thonzylamine, mizolastine, terfenadine, acrivastine, astemizole, azelastine, cetirizine, ebastine, fex chlophendianol, caramiphen, dextromethorphan, diphenhy ofenadine, ketotifen, carbinoxamine, desloratadine, lorata dramine, codeine, hydrocodone, pseudoephedrine, ephe dine, pheniramine, thonzylamine, mizolastine, terfenadine, drine, phenylephrine, phenylpropenolamine, terpin hydrate, chlophendianol, caramiphen, dextromethorphan, diphenhy guaifenesin, potassium, potassium guaicolsulfonate, Cox 2 dramine, codeine, hydrocodone, pseudoephedrine, ephe inhibitors, Celecoxib, Rofecoxib, Valdecoxib, aspirin, drine, phenylephrine, phenylpropenolamine, terpin hydrate, acetaminophen, phenacetin, salicylate salts and combination guaifenesin, potassium, potassium guaicolsulfonate, Cox 2 thereof. inhibitors, Celecoxib, Rofecoxib, Valdecoxib, aspirin, 9. The composition of claim 7, wherein the at least one acetaminophen, phenacetin, salicylate salts and combination second active agent is selected from the group consisting of thereof. chlorpheniramine, dextromethorphan, guaifenesin, acetami 24. The solution of claim 23, wherein the at least one nophen, chlophendianol, diphenhydramine, bromphe second active agent is selected from the group consisting of niramine, loratadine, aspirin and doxylamine Succinate. chlorpheniramine, dextromethorphan, guaifenesin, acetami 10. The composition of claim 1, wherein the composition nophen, chlophendianol, diphenhydramine bromphe is an aqueous based solution. niramine, loratadine, aspirin and doxylamine Succinate. 11. The composition of claim 1, further comprising a 25. The solution of claim 18, further comprising up to buffering agent. about 1.25% w/v citric acid. 12. The composition of claim 11, wherein the buffering 26. The solution of claim 18, further comprising up to agent maintains a pH below about 5.4 in the composition. about 0.2% w/v propyl gallate. US 2007/O 197661 A1 Aug. 23, 2007

27. An aqueous oral pharmaceutical Suspension compo ficial Sweetener, up to about 45% glycerin, and up to about sition comprising: 10% sorbitol, wherein the glycerin to sorbitol ratio is about a). phenylephrine, 2:1 to about 10:1. b). artificial sweetener, 35. The method of claim 34, wherein the pharmaceutical c) a viscosity modifying agent, composition further comprises at least one second active c). up to about 45% w/v glycerin, and agent. 36. The method of claim 35, wherein the second active d). up to about 10% w/v sorbitol wherein the glycerin to agent is selected from the group consisting of analgesics, sorbitol ratio is about 2:1 to about 10:1. decongestants, expectorants, anti-tussives, antipyretics, anti 28. The suspension of claim 27, wherein the viscosity inflammatory agents, cough Suppressants and antihista modifying agent is selected from the group consisting of mines. chitosen, microcrystalline cellulose, Xanthan, HPMC, HPC, 37. An aqueous oral pharmaceutical composition com HEC, galaotomannons and combinations thereof. prising: 29. The suspension of claim 27, wherein the artificial a). an active agent selected from the group consisting of Sweetener is selected from the group consisting of Sucralose, analgesics, decongestants, expectorants, anti-tussives, saccharine salts, cyclamates, acesulfame K, dipeptide based antipyretics, anti-inflammatory agents, cough Suppres Sweeteners, aspartame and mixtures thereof. sants, antihistamines and mixtures thereof; 30. The suspension of claim 27, wherein the artificial b). artificial sweetener; Sweetener comprises sucralose. c). up to about 45% w/v glycerin; and 31. The suspension of claim 27, further comprising an d). up to about 10% w/v sorbitol wherein the glycerin to effective amount of at least a second active agent selected sorbitol ratio is about 2:1 to about 10:1. from the group consisting of analgesics, decongestants, 38. The composition of claim 37, wherein the active agent expectorants, anti-tussives, antipyretics, anti-inflammatory is selected from the group consisting of non-steroidal anti agents, cough Suppressants and antihistamines. inflammatory drugs (NSAIDS), propionic acid derivatives, 32. The suspension of claim 31, wherein the second active ibuprofen, naproxen, ketoprofen, flurbiprofen, fenoprofen, agent is selected from the group consisting of non-steroidal suprofen, fluprofen, fenbufen; acetic acid derivatives, tol anti-inflammatory drugs (NSAIDS), propionic acid deriva metin Sodium, Zomepirac, Sulindac, indomethacin, fenamic tives, ibuprofen, naproxen, ketoprofen, flurbiprofen, feno acid derivatives, mefenamic acid meclofenamate Sodium, biphenyl carboxylic acid derivatives, diflunisal, flufenisal, profen, Suprofen, fluprofen, fenbufen, acetic acid deriva oxicams, piroxicam, Sudoxicam, iSoxicam, chlorphe tives, tolmetin Sodium, Zomepirac, Sulindac, indomethacin, niramine, brompheniramine; dexchlorpheniramine, dexbro fenamic acid derivatives, mefenamic acid meclofenamate mpheniramine, triprolidine, chlorcyclizine, diphenhy sodium, biphenyl carboxylic acid derivatives, diflunisal, flufenisal, oxicams, piroXicam, Sudoxicam, isoxicam, chlo dramine, doxylamine, tripelenamine, cyproheptatine, rpheniramine, brompheniramine; dexchlorpheniramine, bromodiphenhydramine, phenindamine, pyrilamine, azata dexbrompheniramine, triprolidine, chlorcyclizine, diphen dine, acrivastine, astemizole, azelastine, cetirizine, ebastine, fexofenadine, ketotifen, carbinoxamine, desloratadine, lora hydramine, doxylamine, tripelenamine, cyproheptatine, bro tadine, pheniramine, thonzylamine, mizolastine, terfena modiphenhydramine, phenindamine, pyrilamine, azatadine, dine, chlophendianol, caramiphen, dextromethorphan, acrivastine, astemizole, azelastine, cetirizine, ebastine, fex diphenhydramine, codeine, hydrocodone, pseudoephedrine, ofenadine, ketotifen, carbinoxamine, desloratadine, lorata dine, pheniramine, thonzylamine, mizolastine, terfenadine, ephedrine, phenylephrine, phenylpropenolamine, terpin chlophendianol, caramiphen, dextromethorphan, diphenhy hydrate, guaifenesin, potassium, potassium guaicolsul dramine, codeine, hydrocodone, pseudoephedrine, ephe fonate, Cox 2 inhibitors, Celecoxib, Rofecoxib, Valdecoxib, drine, phenylephrine, phenylpropenolamine, terpin hydrate, aspirin, acetaminophen, phenacetin, Salicylate salts and guaifenesin, potassium, potassium guaicolsulfonate, Cox 2 combination thereof. inhibitors, Celecoxib, Rofecoxib, Valdecoxib, aspirin, 39. The composition of claim 38, wherein the active agent acetaminophen, phenacetin, salicylate salts and combination is selected from the group consisting of chlorpheniramine, thereof. dextromethorphan, guaifenesin, acetaminophen, chlophen 33. The suspension of claim 32, wherein the second active dianol, diphenhydramine, brompheniramine, loratadine, agent is selected from the group consisting of chlorphe aspirin, doxylamine Succinate and combinations thereof. niramine, dextromethorphan, guaifenesin, acetaminophen, 40. The composition of claim 39, further comprising an chlorphendianol, doxylamine Succinate and ibuprofen. antioxidant. 34. A method of treating an mammal in need of treatment 41. The composition of claim 40, wherein the antioxidant comprising providing an effective amount of an aqueous oral is propyl gallate. pharmaceutical composition comprising phenylephrine, arti