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US009050289B2

(12) United States Patent (10) Patent No.: US 9,050,289 B2 Mitchell (45) Date of Patent: Jun. 9, 2015

(54) PHARMACEUTICAL COMPOSITIONS A613 L/485 (2006.01) A63L/09 (2006.01) (75) Inventor: Odes W. Mitchell, Arlington, TX (US) A613 L/495 (2006.01) A 6LX3 L/505 (2006.01) (73) Assignee: GM Pharmaceuticals, Inc., Arlington, A6II 45/06 (2006.01) TX (US) (52) U.S. Cl.

c - CPC ...... A6 IK3I/137 (2013.01);s A61 K3I/485 (*) Notice: Sibi E. site th still (2013.01); A61 K3I/495 (2013.01); A61 K p s e s adjusted under 3 1/505 (2013.01); A61K 45/06 (2013.01); .S.C. 154(b) by 28 days. A6 IK3I/09 (2013.01); A61 K3I/4402 (21) Appl. No.: 13/703,584 (2013.01) (58) Field of Classification Search (22) PCT Filed: Jun. 13, 2011 USPC ...... 514/255.04, 653, 275,289, 282,357, 514/352:564/355; 546/74; 544/396, 332 (86). PCT No.: PCT/US2O11?04O231 See application file for complete search history. S371 (c)(1), (2), (4) Date: Feb. 2, 2013 (56) References Cited (87) PCT Pub. No.: WO2011/156822 U.S. PATENT DOCUMENTS PCT Pub. Date: Dec. 15, 2011 2005/0276852 A1 12/2005 Davis et al. 2006/O193877 A1 8/2006 Tengler et al. O O 2008, OO14274 A1 1/2008 Bubnis et al. (65) Prior Publication Data 2008, 0026055 A1 1/2008 Fubara et al. US 2013/0210835A1 Aug. 15, 2013 Primary Examiner — Kristin Vajda Related U.S. Application Data (74) Attorney, Agent, or Firm — Winstead PC (60) Provisional application No. 61/354,053, filed on Jun. 11, 2010, provisional application No. 61/354,057, (57) ABSTRACT Sax"all E. R2.Oal application No. A composition of an antitussive, a , or an anti sw s us • us to treat respiratory and oral pharyngeal congestion (51) Int. Cl. and related symptoms in a patient. A6 IK3I/37 (2006.01) A6 IK3I/4402 (2006.01) 5 Claims, No Drawings US 9,050,289 B2 1. 2 PHARMACEUTICAL COMPOSITIONS toms due to or are often treated with an . , often referred to as histamine CROSS-REFERENCES TO RELATED class receptor blockers, are compounds that may antagonis APPLICATIONS tically block the from binding histamine thereby preventing the symptoms of an . This application claims priority from U.S. Provisional There are many different treatment utilizing a Patent Application No. 61/354,053 filed Jun. 11, 2010, U.S. combination of agents in therapeutic doses for treating mul Provisional Patent Application No. 61/354,057 filed Jun. 11, tiple symptoms of upper respiratory tract and oral pharyngeal 2010, and U.S. 61/354,061 filed Jun. 11, 2010, all of which congestion. As one example, a single may include are hereby incorporated by reference as if fully set forth 10 an expectorant, in combination with an antitussive agent, for herein. removing phlegm or mucus that may have accumulated in the lungs and other air passages in addition to suppressing a FIELD OF THE INVENTION cough. The expectorant is helpful in preventing the progres sion of a mild case of bronchitis to a more severe case of The present invention relates to the treatment and relief of 15 pneumonia. various symptoms of upper respiratory and oral pharyngeal Combination therapy provides many benefits. For congestion, and in particular, to a combination medication for example, it allows patients Suffering from congestion and treatment and relief thereof. related symptoms to take only a single dosage medication, as opposed to multiple medications, for relief therefrom. Fur BACKGROUND OF THE INVENTION ther, it enhances compliance in accordance with a regimen by eliminating the need for the patient to take different medica People around the world frequently suffer from upper res tions. To this end, combination therapy provides conve piratory tract and oral pharyngeal congestion. This conges nience, ensures compliance, and saves cost. tion may be caused by allergies, infections in the respiratory Combined treatment medications may be formulated as tract and/or oral and pharyngeal cavities, changes in weather 25 syrups, pills, tablets, and capsules. Formulations may include conditions, as well as from the overall health and genetic flavoring agents to mask undesirable flavors or tastes from disposition of the person. This congestion is generally diag desired medicinal agents and colorants to render the medica nosed from partially or fully blocked air passages including tion more attractive and appealing to the eye. For example, airways in the lungs, mouth, nose, and throat. Other symp many formulations have a raspberry, cherry, orange, or grape toms related to the cause typically accompany the congestion. 30 flavor well liked by both children and adults. Moreover, these Cough, tickles in the throat, cold symptoms such as fever, flu, flavors are easily identified by their color. In combination sinus infections, and throat or gland pain are some of the more formulations, the individual ingredients are included in common symptoms found with upper respiratory and oral amounts proven to be effective to treat targeted symptoms. pharyngeal congestion. Effective amounts have varied depending on the particular Congestion of the upper respiratory tract and oral pharyn 35 formulation, type and degree of the symptoms, and desired geal cavity and related symptoms generally have undesirable user or consumer. For example, a child's dose of an elixir or effects for the afflicted person. For example, the congestion syrup for the relief of cough and pain related to congestion may affect performance in the workplace, School, and at may have the antitussive and in reduced quantities home up to and including loss of work and loss of School based on size, weight, and age of the child targeted, compa attendance. Further, congestion may reduce the ability to 40 rable to a composition or formulation for an adult which may perform routine activities, such as housework, driving, run have double the dosage of the antitussive and analgesic. ning errands, and may even totally incapacitate the person. Accordingly, it is desirable to have an administrable com Severe and intolerable congestion often requires visits to the position to reduce symptoms of upper respiratory tract and hospital and treatment. In addition, viral or bacterial infec oral pharyngeal congestion. It is further desirable that the tions of the sinus passage or other airway may be passed to 45 composition be effective in reducing cough, congestion, his healthy persons through symptoms of the congestion. For tamine-stimulated allergy symptoms and related pain. Still example, a cough or Sneeze may convey a bacterium or virus further, it is desirable for the composition to contain dosages to another person. Thus, upper respiratory tract and oral pha suitable for administration to a child as well as an adult. In ryngeal congestion and its symptoms need to be treated. addition, it is desirable to have the composition in a conve Generally, there are two typical approaches to treating 50 nient and pharmaceutically acceptable dosage form. symptoms of the congestion. One approach involves initially treating the underlying cause of the symptom. For example, a SUMMARY OF THE INVENTION bacterial infection is generally treated by administering an antibiotic to kill the bacteria causing the infection. The sec The present invention provides compositions and methods ond approach involves treating the symptoms themselves, 55 for treating upper respiratory and oral pharyngeal congestion typically in addition to treating the underlying cause, by and related symptoms in a person Suffering therefrom. To this independently administering one or more medications for end, and in accordance with the principles of the present relief of specific symptoms. For example, an antitussive invention, there is provided a composition of a decongestant, agent, commonly referred to as a cough suppressant, has been and an antihistamine. Optionally, a composition may include typically administered for the treatment or relief of cough. An 60 an antitussive, an expectorant and an analgesic. The combi medication, Such as and bitar nation of an antitussive, a decongestant, and an antihistamine trate, has generally been administered to relieve pain consis in a single composition provides relief of cough, congestion tent with the congestion while Suppressing a cough. Also in the air passageways, and common allergy-type symptoms , such as and , resulting from exposure to various allergens, in a convenient have been administered to both children and adults inflavored 65 and effective dosage formulation. formulations for reducing mucosal Swelling and draining the The composition is formulated in pharmaceutically accept mucus build-up to clear congestion in the airpassages. Symp able forms such as liquids, pills, capsules, tablets, and the US 9,050,289 B2 3 4 like. Suitable capsule forms include, without limitation, liq tant provides relief of histamine-stimulated allergy Symp uid gelatin capsules and enteric-coated capsules. The tablet toms in addition to relieving other symptoms, such as cough, form may be chewable, may melt or disintegrate in the mouth, congestion, Swelling, and pain. These added benefits provide or may be enteric-coated to provide delayed-release and Sus increased efficacy and translate into convenience and cost tained-release characteristics for the composition. In one savings for the patient. embodiment, the composition is formulated into a liquid. The The present invention provides pharmaceutical composi composition may further include other components, such as tions containing an antihistamine along with a decongestant conventional excipients including binders, colorants, fra and optionally an analgesic or an antitussive. The composi grances, and the like, to render the composition more attrac tions of the invention may be administered in effective dos tive and suitable for use. 10 ages for treating nasal congestion symptoms. To this end, the By virtue of the foregoing, there is thus provided compo pharmaceutical compositions include at least one antihista sitions and methods for treating upper respiratory and oral mine and at least one stimulant. The most potent antihista pharyngeal congestion and related symptoms in effective for mines are generally sedating in nature and the sedation is mulations. These and other benefits and advantages of the reduced or alleviated with the stimulant. The compositions present invention shall be made apparent from the accompa 15 are useful for treating allergic reactions and other histamine nying detailed description thereof. mediated symptoms, as well as for providing other physi ological effects including, for example, DETAILED DESCRIPTION OF EXEMPLARY effects, analgesic effects, effects, Soporific EMBODIMENTS effects, anti-secretory effects, and combination effects thereof. By combining a potent, effective antihistamine with The present invention provides compositions and methods an effective, anti-sedating stimulant, the compositions of the for treating upper respiratory and oral pharyngeal congestion present invention may be administered more safely than prior and related symptoms in a patient in need thereof. The term art antihistamine-containing medications utilized for the “upper respiratory and oral pharyngeal congestion' as used same purpose. The present invention also provides methods herein includes congestion in the oral, pharyngeal, nasal, and 25 of use for the pharmaceutical compositions. bronchial passages of the upper respiratory tract. It also is Antihistamines Suitable for the compositions include, intended to include other symptoms, such as cough and pain without limitation, , hydro related to allergies, infections, colds, coughs, flu, viral and chloride, brompheneramine, hydroxy Zine, chlorophe bacterial infections, and other common causes for the con niramine, pyrilamine maleate, pyrilamine tannate, acepro gestion. Thus, multiple symptoms including congestion may 30 mazine, aceprometazine, , alimemazine tartrate, be treated with the compositions of the present invention. amoxydramine camsilate, chlorhydrate, antaZo Treatment includes a reduction in severity or duration, delay line mesilate, antazoline phosphate, , in onset, and/or general relief of one or more of these symp dimaleate, hydrochloride, hydrochlo toms. The term is intended to refer to congestion as described ride, hydrochloride, bretylium tosilate, bro herein, as well as to a wide range of symptoms related to the 35 mazine hydrochloride, maleate, congestion or its cause and treatable with the present compo dihydrochloride, bufeXamac, maleate acid, sitions. For example, symptoms related to a common cold or cetiedil citrate, dihydrochloride, flu Such as cough, fever, and the like, and allergy symptoms hydrochloride, maleate, Such as , breakouts, Swelling, and runny nose due to hydrochloride, hydrochloride, , external stimulants are treated with the present compositions. 40 fumarate, hexachlorophenate, clemi In addition, symptoms, such as congestion, cough, pain and Zole penicilline, clemizole undecylenate, dihy discomfort associated with the congestion, resulting from a drochloride, clo?edanol, clofenetamine hydrochloride, bacterial or viral infection, particularly an infection in the hydrochloride, maleate, respiratory tract, are also treated with the present composi di (acefylline)diphenhydramine, difencloxazine, dimelazine tions. The term “congestion', as use herein, is intended to 45 hydrochloride, , dimethoxanate hydrochlo refer to the narrowing of an airway including the oral, pha ride, cimetotiazine mesilate, diphenhydramine hydrochlo ryngeal, nasal and bronchial passages due to fluid or a solid ride, diphenhydramine mesilate, hydro Substance, such as mucus orphlegm. Narrowing of the airway chloride, diprocqualone camsilate, , is often due to Swelling or inflammation of the mucous mem Succinate, eproZinol dihydrochloride, dimale brane lining the passage to resultina partially or fully blocked 50 ate, bromhydrate, etybenzatropine hydro passage. Severe cases of congestion often cause difficulties in chloride, hydrochloride, hydro breathing. Besides allergic reactions, infections, and com chloride, hydrochloride, fenpentadiol, mon cold and flu, the symptoms described herein may also be hydrochloride, decanoate, flupentixol due to poor health or a predisposition for the symptom dihydrochloride, hydrochloride, through genetic make-up. The terms “treating and “alleviat 55 dihydrochloride, hydroxyzine embonate, indoramine hydro ing', as used herein with respect to upper respiratory and oral chloride, hydrochloride, ketotifene fumarate, pharyngeal congestion and related symptoms, include any hydrochloride, , levomepro reduction in severity or duration, of any degree, of the con mazine hydrochloride, levomepromazine embonate, levome gestion and/or one or more of the related symptoms. The maleate, , hydrochloride, terms also include any delays in onset of and any general 60 maprotiline mesilate, maprotiline resinate, meclozine hydro relief from the congestion and/or one or more of the related chloride, mecysteine hydrochloride, fuma symptoms. Thus, the present invention encompasses pallia rate, mefenidramium metilsulfate, maleate, tive compositions and methods. meduitazine, methaqualone, hydrochloride, To this end, and in accordance with the principles of the hydrochloride, , moxisylyte hydrochlo present invention, the compositions include an antitussive, a 65 ride, , hydrochloride, oxaflumazine decongestant, and an antihistamine. Inclusion of an antihis disuccinate, , oxolamine benzilate, oxolamine cit tamine, in combination with an antitussive and a deconges rate, , oXomemazine hydrochloride, parathiaz US 9,050,289 B2 5 6 ine teoclate, perimetazine, maleate, phenoxy erties, ingredients imparting desirable and acceptable benzamine hydrochloride, , hardness, disintegration properties, dissolution rate for phenyltoloxamine citrate, , , piprete release of therapeutic components, stability, and size to effec col dihydrochloride, pizotifene malate, prednazoline, profe tively deliver the composition may be included. Disintegrants namine hydrochloride, , promethazine hydro may be included for the purposes of facilitating the breakup of chloride, promethazine embonate, promethazine a tablet after the tablet is administered to the patient. polyvinylbenzene-metacrylate, , , Examples of disintegrants include, but are not limited to, tartrate, hydrochloride, thiazina modified or unmodified Starches such as cornstarch, potato mium metilsulfate, hydrochloride, tripelen starch, wheat starch, or sodium cross-carmellos. With respect namine hydrochloride, hydrochloride, and tyma 10 to aesthetics, it may be desirable for the composition to con Zoline hydrochloride, and combinations thereof. tain additives that appeal to the human senses such as colo The antihistamine is included in an amount, per dosage of rants, fragrances, texture modifiers, and/or flavorants. Addi the composition, Sufficient to alleviate one or more histamine tionally, many flavoring agents such as, for example, fruit mediated responses in a patient. Effective doses of the anti flavors, or Sweeteners, such as Sodium saccharin, confection histamine will generally vary depending upon the antihista 15 ery Sugar, Sucrose, Xylitol, or combinations thereof, may be mine (S) administered. included. Additionally, Suitable colorants including, for The present composition also includes an antitussive. The example, red beet powder, ferric oxide, FD&C dyes, or com term “antitussive’, as used herein, is intended to include any binations thereof, may be included in the present composi agent or active ingredient effective for cough Suppression tions. Desirable excipients may also include buffering agents, such as chlophedianol hydrochloride. These also include, but Surfactants, electrolytes, and thixotropic agents. It should be are not limited to, common opioid such as hydro understood that these other components should not affect the codone, codeine, , morphine-related compounds action or mechanism of action of the antitussive, deconges including diacetylmorphine, , , tant, and/or the antihistamine in the composition. , , , nalmefene, Excipients or formulations affecting the release properties, , meperidine, , , nalbu 25 mechanisms, and/or rates of the antitussive, the decongestant, phine, , Sufentanyl, alfentanyl and pro and the antihistamine, from the composition upon oral inges poxyphene, and opioid antagonists not structurally-related to tion may be provided. For example, the composition may be morphine, such as nalorphine, naloxone, naltrexone and fen formulated such that the release of the antitussive, the decon tanyl. In one embodiment, the antitussive agent is hydroc gestant, and/or the antihistamine or other active ingredients odone or a pharmaceutically acceptable Salt form thereof, 30 from the composition is delayed for a period of time or to Such as hydrocodone bitartrate. Survive a particular environment. The present composition also includes a decongestant. The Advantageously, the composition may be formulated so as term “decongestant as used herein, is intended to refer to any to prevent the release of the antitussive, the decongestant, agent or ingredient, active for reducing or eliminating con and/or the antihistamine in the stomach where they may likely gestion of the air passages by widening the airway, and/or by 35 be acidified, salted out and excreted from the body rather than stimulating the release of phlegm and mucus from these pas absorbed into the circulation. For example, the composition sages. Airpassages may be widened by reducing the Swelling may be coated with a coating to improve absorption and of the mucous membranes in the passage. Generally, sym render the composition more bioavailable than it would oth pathomimetic drugs have decongestant properties. Examples erwise be without the coating. Enteric coatings or encapsula of suitable decongestants include, without limitation, phenyl 40 tion-type coatings as known to one skilled in the art are ethylamine, epinephrine, norepinephrine, , dob suitable for this purpose. In one embodiment, a table or a utamine, colterol, ethylnorepinephrine, isoproterenol, isoet capsule form of the composition is enterically coated so as to harine, metaproterenol, terbutaline, metaraminol, provide delayed-release and Sustained-release properties to phenylephrine, tyraine, hydroxyamphetamine, ritodrine, the composition. Sustaining the release of individual active prenalterol, methoxyamine, albuterol, , meth 45 ingredients to the body over a period of time prolongs the amphetamine, benzphetamine, , phenylpropanola effective time period of relief from the congestion and related mine, mephentermine, phentermine, , propyl symptoms, provided, however, the amount of the ingredient hexedrine, diethylpropion, phenmetrazine, phendimetrazine, in the blood stream is within the effective therapeutic window , , and pseudoephedrine. for that particular ingredient. Further, preservatives may be It should be understood that an effective amount of the 50 provided to prevent degradation of components in the com antitussive and the decongestant generally vary with the par position or degradation of the composition as a whole, ticular antitussive and decongestant chosen. In addition, an thereby improving the stability and prolonging the shelf life effective amount depends upon many other factors, such as of the composition. known differences in pharmacokinetic parameters (absorp The composition of the present invention may be formu tion, distribution and clearance) regardless of the cause. For 55 lated in a single form. In one embodiment, the form is con example, in a patient with a renal dysfunction or disorder, the Venient to Swallow, and has a generally accepted appearance effective dose of the antihistamine, the antitussive, and the and taste to promote consumption and compliance with a decongestant is generally half of an effective dose for a dosing regimen. In accordance with one aspect of the present patient without renal dysfunction. invention, the composition is formulated into a dosage form While the present composition includes an antitussive, a 60 that may be an ingestible liquid, a pill, a tablet, a capsule, a decongestant, and an antihistamine, the present composition Suppository, etc. In accordance with another aspect of the is not so limited and may include other components. These invention, the composition may beformulated into a parenter components include conventional excipients, useful and/or ally administrable form. It should be understood by one desirable to render the composition suitable or attractive for skilled in the art that certain active agents, such as hydroc consumption and use. Excipients providing physical and aes 65 odone, are typically not parenterally administered, such as by thetic properties for formulation or delivery of the composi intra-venous administration. However, other such as tion are desirable. For example, with respect to physical prop codeine, morphine, methadone, and may be admin US 9,050,289 B2 7 8 istered with antihistamine in a non-orally administrated for diagnosis will generally influence the amounts administered. mulation. In accordance with a further aspect of the invention, The composition is generally administered for alleviating the present composition may include active ingredients Suit cough, pain, cold and allergy symptoms and also provides a able for Sub-lingual administration. In accordance with yet sedative effect, an analgesic adjuvant effect, an anticholin another aspect of the invention, the present composition may ergic affect, and a mild analgesic effect. Formulations of the invention may contain any or all of the be administered via mucous membranes of the buccal, nasal, following in any combination: Purified Water, Any combina rectal cavities, etc. The desired formulation may be prepared tion of permitted API's added as powders or as solutions, by a process known in the art of pharmaceutical manufacture. emulsions, Suspensions: Chlophedianol Hydrochloride, For example, liquid formulations may be prepared in the form Pseudoephedrine Hydrochloride, Phenylephrine, or any of a syrup or a Suspension. In one embodiment, the compo 10 approved oral nasal decongestant: Dexchlorpheniramine sition is formulated into an elixir or a syrup having a desirable Maleate, Maleate, Brompheniramine flavor for easy, trouble-free administration to a child. Maleate, Chlorcyclizine Hydrochloride, Thonzylamine Solid formulations, such as capsules may be prepared by Hydrochloride, Pyrilamine Maleate, Tartrate, first blending the antitussive, the decongestant, and the anti or any approved oral antihistamine; Guaifenesin or any histamine with other desirable additives and then filling cap 15 approved oral expectorant, Acetaminophen or any approved Sular materials with the blended mixture using conventional analgesic, antipyretic or anti-inflammatory; Citric Acid; filling equipment. In one embodiment, the capsular material Sodium Citrate; Propylene Glycol; Flavor, Sodium Saccharin is a gelatin. The capsule formed may be a liquid gelatin Solution (Sodium Saccharin dissolved in water or any other capsule. Further, where desired, the capsule may be coated for solvent); Sorbitol; Glycerin; and Purified Water. added benefits. In general, tablets may be formed by first The formulations of the invention may be combined with blending the components and then either directly compress any of the following pharmaceutical aids or excipients or ing the blended components, or granulating the components preservatives, added as solutions, Suspension, emulsions, or followed by compressing them into a tablet form. Additional directly added as liquids or powders: Preservatives-including ingredients may be included during compression where but not limited to the following: Parabens, Benzoates, Sor desired. For example, the granular mixture may contain one 25 bates: Artificial Sweeteners-including but not limited to the or more lubricants to inhibit sticking during compression. following: Sucralose, Saccharin, Acesulfame; Sweeteners Examples of suitable lubricants include, but are not limited to, including but not limited to the following: Sucrose, Corn Stearic acid, palmetic acid, Stearates, talc, and oils. Syrup, High Fructose Corn Syrup, Maltitol, Mannitol, Dex The compositions of the invention may also be formulated trose, Glucose: Thickeners-including but not limited to the as a powder or sprinkles. 30 following: Gums, Mucilages, Xanthan Gum, Guar Gum, Vee To effectively suppress cough, relieve pain, and reduce gum, Methylcellulose Derivatives; Buffering Agents-includ mucus membrane Swelling for reducing congestion and other ing but not limited to the following: Phosphates, Citrates, blockage of air passages, the composition of the present Sulfates, Carbonates, etc.; and Alcohol Derivatives invention includes the antitussive, the decongestant, and the as Solvents, Preservatives, Flavors: Emulsifiers; Coloring antihistamine in amounts suitable for treating children and 35 Agents, Dyes, Certified Colors: Any and all pharmaceutical adults alike. excipients. In yet another embodiment of the present invention, there is While the present invention has been illustrated by the provided methods of alleviating symptoms of upper respira description of embodiments thereof, and while the embodi tory and oral pharyngeal congestion by orally administering ments have been described in considerable detail, it is not to a patient in need thereof a single dose of a composition or 40 intended to restrict or in any way limit the scope of the formulation including an antitussive, a decongestant, and an appended claims to Such detail. Additional advantages and antihistamine. The patient in need may be a child or an adult modifications will be readily apparent to those skilled in the Suffering from the congestion. Administration of the compo art. The invention in its broader aspects is, therefore, not sition will depend upon the form of the composition. For limited to the specific details, representative method, and example, a liquid formulation may be administered to a child 45 illustrated examples described. Accordingly, departures may in amounts Smaller than that administered to an adult. Admin be made from Such details without departing from the scope istration will also depend upon various other factors related to or spirit of Applicant's general inventive concept. the patient. For example, age, health, weight, prior medical Examples of the compositions of the invention are set forth history, extent and degree of symptoms, and overall medical below:

ACTIVE 1 ACTIVE 2 ACTIVE 3 hilophedianol H Pseudoephedrine HCl 30 mg Dexchlorpheniramine Maleate 1 mg hilophedianol H Pseudoephedrine HCl 30 mg Guaifenesin 100 mg hilophedianol H Pseudoephedrine HCL 30 mg Guaifenesin 200 mg hilophedianol H Pseudoephedrine HCl 30 mg Chlorcyclizine 9.375 mg hlorcyclizine H Pseudoephedrine HCl 30 mg hlophendiano C 5 l 9. Guaifenesin 200 mg hlorcyclizine H : Pseudoephedrine HCl 30 mg hlorcyclizine H Pseudoephedrine HCl 30 mg Codeine Phosphate 10 mg hlorcyclizine H Codeine Phosphate 10 mg hilophedianol H Dexbrompheniramine 1 mg Phenylephrine HCl 5 mg hilophedianol H Pseudoephedrine HCl 60 mg Chlorpheniramine Maleate 4 mg hlorcyclizine H Pseudoephedrine HCl 30 mg Chlophedianol HCl 12.5 mg hlorcyclizine H Pseudoephedrine HCl 30 mg Dextromethorphan HBr 15 mg hilophedianol H Guaifenesin 100 mg Phenylephrine HCl 5 mg honzylamine H Codeine Phosphate 10 mg honzylamine H Codeine Phosphate 10 mg Pseudoephedrine HCl 30 mg US 9,050,289 B2 10 -continued

AC T VE1 ACTIVE 2 ACTIVE 3 hedianol HCl 12.5 mg Pseudoephedrine HCl 30 mg hedianol HCl 12.5 mg Dexbrompheniramine 1 mg Phenylephrine HCl 5 mg hedianol HCl 12.5 mg Pseudoephedrine HCl 30 mg Brompheniramine Maleate 2 mg hedianol HCl 12.5 mg Pseudoephedrine HCl 30 mg Chlorcyclizine 9.375 mg hedianol HCl 25 mg Pseudoephedrine HCl 60 mg Chlorcyclizine 18.75 mg hedianol HCl 12.5 mg Phenylephrine HCl 5 mg Chlorcyclizine 9.375 mg hedianol HCL 25 mg Phenylephrine HCl 10 mg Chlorcyclizine 18.75 mg hendianol HCI 25 mg Pseudoephedrine HCl 60 mg Pyrilamine maleate 50 mg hendianol HCI 25 mg Phenylephrine HCl 10 mg Guaifenesin 200 mg hendianol HCI 25 mg Phenylephrine HCl 10 mg Guaifenesin 400 mg hendianol HCl 12.5 mg Guaifenesin 100 mg hendianol HCl 12.5 mg Pseudoephedrine HCl 30 mg Thonzylamine HCl 50 mg hendianol HCI 25 mg Pseudoephedrine HCl 60 mg Thonzylamine HCl 100 mg hendianol HCl 12.5 mg Phenylephrine HCl 5 mg Thonzylamine HCl 50 mg hendianol HCI 25 mg Phenylephrine HCl 10 mg Thonzylamine HCl 100 mg hendianol HCI 25 mg Guaifenesin 400 mg phendianol HCI 25 mg Pseudoephedrine HCl 60 mg Guaifenesin 400 mg orcyclizine HC19.375 Phenylephrine HCl 5 mg orcyclizine HCI 18.75 mg Phenylephrine HCl 10 mg orcyclizine HCI 18.75 mg Pseudoephedrine HCl 60 mg honzylemine HCl 50 mg Pseudoephedrine HCl 30 mg honzylemine HCl 100 mg Pseudoephedrine HCl 60 mg honzylemine HCl 50 mg Phenylephrine HCl 5 mg honzylemine HCl 100 mg Phenylephrine HCl 10 mg hlorcyclizine HCl 9.375 mg Pseudoephedrine HCl 30 mg Acetaminophen 325 mg honzylemine HCl 50 mg Pseudoephedrine HCl 30 mg Acetaminophen 325 mg hlorcyclizine HCI 18.75 mg Pseudoephedrine HCl 60 mg Acetaminophen 500 mg honzylemine HCl 100 mg Pseudoephedrine HCl 60 mg Acetaminophen 500 mg hlophendianol HCl 12.5 mg Pseudoephedrine HCl 30 mg Thonzylamine HC 50 mg hlophendianol HCI 25 mg Pseudoephedrine HCl 60 mg Thonzylamine HC 100 mg hlophendianol HCl 12.5 mg Phenylephrine HCl 5 mg Thonzylamine HC 50 mg hlophendianol HCI 25 mg Phenylephrine HCl 10 mg Thonzylamine HC 100 mg hlophendianol HCl 12.5 mg Phenylephrine HCl 5 mg Chlorcyclizine HC 9.375 mg hlophendianol HCI 25 mg Phenylephrine HCl 10 mg Chlorcyclizine HC 18.75 mg hilophendianol HCl 25 mg Pseudoephedrine HCL 60 mg Guaifenesin 200 m8. hlophendianol HCI 25 mg Phenylephrine HCl 10 mg Brompheniramine 4 mg hlorcyclizine HCl 9.375 mg Codeine Phosphate 10 mg Pseudoephedrine HCl 30 mg hlorcyclizine HCl 9.375 mg Codeine Phosphate 10 mg Acetaminophen 325 mg honzylamine HCl 50 mg Codeine Phosphate 10 mg Pseudoephedrine HCl 30 mg honzylamine HCl 50 mg Codeine Phosphate 10 mg Acetaminophen 325 mg honzylamine HCl 50 mg Codeine Phosphate 10 mg Phenylephrine HCl 5 mg hlorcyclizine HCl 9.375 mg Codeine Phosphate 10 mg Phenylephrine HCl 5 mg hlorcyclizine HCl 9.375 mg Codeine Phosphate 10 mg Phenylephrine HCl 5 mg honzylamine HCl 50 mg Codeine Phosphate 10 mg Phenylephrine HCl 5 mg hlophendianol HCl 12.5 mg Pseudoephedrine HCl 30 mg Chlorpheniramine Maleate 2 mg hlophendianol HCl 12.5 mg Pseudoephedrine HCl 30 mg Dexbrompheniramine Maleate 1 mg honzylamine HCl 50 mg Pseudoephedrine HCl 30 mg Dextromethorphan HBr 15 mg honzylamine HCl 50 mg Phenylephrine HCl 5 mg Dextromethorphan HBr 15 mg hlorcyclizine HCl 9.375 mg Pseudoephedrine HCl 30 mg Dextromethorphan HBr 15 mg hlorcyclizine HCl 9.375 mg Phenylephrine HCl 5 mg Dextromethorphan HBr 15 mg hlophedinol HCl 12.5 mg Pseudoephedrine HCl 30 mg Guaifenesin 75 mg hlorcyclizine HCl 9.375 mg Pseudoephedrine HCl 30 mg Dextromethorphan HBr 15 mg honzylamine HCl 50 mg Phenylephrine HCl 5 mg Dextromethorphan HBr 15 mg hlophendianol HCL 12.5 mg Phenylephrine HCl 5 mg Guaifenesin 200 mg hlophendianol HCl 12.5 mg Pseudoephedrine HCl 30 mg Pyrilamine Maleate 25 mg hlophendianol HCl 12.5 mg Phenylephrine HCl 5 mg Pyrilamine Maleate 25 mg hlophendianol HCl 12.5 mg Pseudoephedrine HCl 30 mg Guaifenesin 100 mg hlophendianol HCI 25 mg Pseudoephedrine HCl 60 mg Guaifenesin 200 mg hlophendianol HCl 12.5 mg Phenylephrine HCl 5 mg Guaifenesin 100 mg hlophendianol HCI 25 mg Phenylephrine HCl 10 mg Guaifenesin 200 mg hlophendianol HCI 25 mg Pseudoephedrine HCl 60 mg Guaifenesin 400 mg hlophendianol HCI 25 mg Phenylephrine HCl 10 mg Guaifenesin 400 mg hlophendianol HCl 12.5 mg Pseudoephedrine HCl 30 mg Guaifenesin 200 mg hlophendianol HCl 12.5 mg Phenylephrine HCl 5 mg Guaifenesin 200 mg hlophendianol HCl 12.5 mg Pseudoephedrine HCl 30 mg Doxylamine Succinate 6.25 mg hlophendianol HCl 12.5 mg Pseudoephedrine HCl 30 mg Doxylamine Succinate 6.25 mg hlophendianol HCl 12.5 mg Phenylephrine HCL 5 mg Doxylamine Succinate 6.25 hlophendianol HCl 12.5 mg Phenylephrine HCl 5 mg Doxylamine Succinate 6.25 mg hlophendianol HCl 12.5 mg Pseudoephedrine HCl 30 mg Diphenhydramine HCI 25 mg hlophendianol HCl 12.5 mg Phenylephrine HCl 5 mg Diphenhydramine HCI 25 mg hlophendianol HCl 12.5 mg Pseudoephedrine HCl 30 mg Diphenhydramine HCI 25 mg hlophendianol HCl 12.5 mg Phenylephrine HCl 5 mg Diphenhydramine HCI 25 mg hlophendianol HCl 12.5 mg Guaifenesin 200 mg hlophendianol HCl 8.33 mg Brompheniramine 1.33 mg Phenylephrine 33.33 mg hlorcyclizine HCI 25 mg Pseudoephedrine HCl 60 mg Codeine Phosphate 10 mg honzylamine HCl 100 mg Pseudoephedrine HCl 60 mg Codeine Phosphate 10 mg hlorcyclizine HCI 25 mg Pseudoephedrine HCl 60 mg US 9,050,289 B2 11 12 -continued

ACTIVE 1 ACTIVE 2 ACTIVE 3 Chlorcyclizine HCI 25 mg Chlophedianol HCI 25 mg Chlorcyclizine HCI 25 mg Chlophedinol HCl 25 mg Pseudoephedrine HCl 60 mg Chlorcyclizine HCI 25 mg Chlophedianol HCl 12.5 mg Chlophedianol HCI 25 mg Thonzylamine HCl 100 mg Codeine Phosphate 10 mg Thonzylamine HCl 100 mg Pseudoephedrine HCl 60 mg Dextromethorphan HBr30 mg Thonzylamine HCl 100 mg Pseudoephedrine HCl 60 mg Dextromethorphan HBr 15 mg Thonzylamine HCl 100 mg Pseudoephedrine HCl 60 mg Dextromethorphan HBr 20 mg Chlorcyclizine HCI 25 mg Pseudoephedrine HCl 60 mg Dextromethorphan HBr30 mg Dextromethorphan HBr 15 mg Chlorcyclizine HCl 9.373 Dextromethorphan HBr30 mg Chlorcyclizine HCl HBr 18.75 mg Dextromethorphan HBr 15 mg Thonzylamine HCl 50 mg Dextromethorphan HBr30 mg Thonzylamine HCl 100 mg Chlophedianol HCl 12.5 mg Thonzylamine HCl 50 mg Chlophedianol HCl 12.5 mg Chlorcyclizine HCl 9.375 mg

What is claimed is: 20 consisting of Dexchlorpheniramine Maleate, Pyrilamine 1. A pharmaceutical composition for alleviating symptoms maleate, Diphenhydramine HCl, Codeine phosphate, Doxy of upper respiratory and oral-pharyngeal congestion in a Sub lamine Succinate, and Guaifenesin. ject, the composition comprising a first active ingredient 3. The pharmaceutical composition of claim 1, wherein the selected from the group consisting of chlophedianol hydro first active ingredient is present at a range of 9.375 mg to 100 chloride, chlorcyclizine hydrochloride, and thonzylamine 25 ng. hydrochloride; and 4. The pharmaceutical composition of claim 1, wherein the a second active ingredient selected from the group consist second active ingredient is present at a range of 1 mg to 100 ing of Pseudoephedrine Hydrochloride, Guaifenesin, ng. Codeine phosphate, Dexbrompheniramine, and thonzy 5. The pharmaceutical composition of claim 2, wherein lamine hydrochloride. 30 2. The pharmaceutical composition of claim 1, further third active ingredient is presentata range of 2 mg to 500 mg. comprising a third active ingredient selected from the group k k k k k