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Home , Astemizole, Chlorcyclizine, Chlorphenoxamine, Clofedanol, Dexbrompheniramine, Thenalidine

US 20130210835A1 (19) United States (12) Patent Application Publication (10) Pub. N0.2 US 2013/0210835 A1 Mitchell (43) Pub. Date: Aug. 15, 2013

(54) PHARMACEUTICAL COMPOSITIONS Publication Classi?cation (75) Inventor: Odes W. Mitchell; Arlington, TX (U S) (51) Int. Cl. A61K31/137 (2006.01) _ A611; 31/4402 (2006.01) (73) Ass1gnee: GM PHARMACEUTICAL, INC, A61K 31/485 (200601) Arhngton, TX (Us) A611; 31/09 (2006.01) _ A611; 31/495 (2006.01) (21) App1.No.. 13/703,584 A61K31/505 (200601) 22 PCT P1 d: J .13 2011 (52) us Cl ( ) 1e “n ’ CPC ...... A611; 31/137 (2013.01); A611;31/495 (86) PCT NO. PCT/“11,4031 (2013.01); A611;31/505 (2013.01); A611; 31/485 (2013.01); A611; 31/09 (2013.01); § 371 (0)0). A611;31/4402 (2013.01) (2), (4) Date: Feb- 2, 2013 USPC ...... 514/255.04; 564/355; 514/653; 544/396; 544/332; 514/275; 546/74; 514/289; 514/282; Related US. Application Data 514657; 514652 (60) Provisional application No. 61/354,061; ?led on Jun. (57) ABSTRACT 11; 2010; provisional application No. 61/354,057; A composition of an antitussive; a ; or an anti ?led on Jun. 11; 2010; provisional application No. to treat respiratory and oral pharyngeal congestion 61/354,053; ?led on Jun. 11,2010. and related symptoms in a patient. US 2013/0210835 A1 Aug. 15,2013

PHARMACEUTICAL COMPOSITIONS mucus build-up to clear congestion in the air passages. Symp toms due to or are often treated With an CROSS-REFERENCES TO RELATED . , often referred to as histamine APPLICATIONS class receptor blockers, are compounds that may antagonis tically block the from binding histamine [0001] This application claims priority from US. Provi thereby preventing the symptoms of an . sional Patent Application No. 61/354,053 ?led Jun. 11, 2010, US. Provisional PatentApplication No. 61/354,057 ?led Jun. [0006] There are many different treatment uti 11, 2010, and US. 61/354,061 ?led Jun. 11, 2010, all of liZing a combination of agents in therapeutic doses for treat Which are hereby incorporated by reference as if fully set ing multiple symptoms of upper respiratory tract and oral forth herein. pharyngeal congestion. As one example, a single may include an expectorant, in combination With an antitus FIELD OF THE INVENTION sive agent, for removing phlegm or mucus that may have accumulated in the lungs and other air passages in addition to [0002] The present invention relates to the treatment and suppressing a cough. The expectorant is helpful in preventing relief of various symptoms of upper respiratory and oral the progression of a mild case of bronchitis to a more severe pharyngeal congestion, and in particular, to a combination case of pneumonia. medication for treatment and relief thereof. [0007] Combination therapy provides many bene?ts. For example, it alloWs patients suffering from congestion and BACKGROUND OF THE INVENTION related symptoms to take only a single dosage medication, as [0003] People around the World frequently suffer from opposed to multiple medications, for relief therefrom. Fur upper respiratory tract and oral pharyngeal congestion. This ther, it enhances compliance in accordance With a regimen by congestion may be caused by allergies, infections in the res eliminating the need for the patient to take different medica piratory tract and/or oral and pharyngeal cavities, changes in tions. To this end, combination therapy provides conve Weather conditions, as Well as from the overall health and nience, ensures compliance, and saves cost. genetic disposition of the person. This congestion is generally [0008] Combined treatment medications may be formu diagnosed from partially or fully blocked air passages includ lated as syrups, pills, tablets, and capsules. Formulations may ing airWays in the lungs, mouth, nose, and throat. Other include ?avoring agents to mask undesirable ?avors or tastes symptoms related to the cause typically accompany the con from desired medicinal agents and colorants to render the gestion. Cough, tickles in the throat, cold symptoms such as medication more attractive and appealing to the eye. For fever, ?u, sinus infections, and throat or gland pain are some example, many formulations have a raspberry, cherry, orange, of the more common symptoms found With upper respiratory or grape ?avor Well liked by both children and adults. More and oral pharyngeal congestion. over, these ?avors are easily identi?ed by their color. In com [0004] Congestion of the upper respiratory tract and oral bination formulations, the individual ingredients are included pharyngeal cavity and related symptoms generally have in amounts proven to be effective to treat targeted symptoms. undesirable effects for the a?llicted person. For example, the Effective amounts have varied depending on the particular congestion may affect performance in the Workplace, school, formulation, type and degree of the symptoms, and desired and at home up to and including loss of Work and loss of user or consumer. For example, a child’s dose of an elixir or school attendance. Further, congestion may reduce the ability syrup for the relief of cough and pain related to congestion to perform routine activities, such as houseWork, driving, may have the antitussive and in reduced quantities running errands, and may even totally incapacitate the person. based on siZe, Weight, and age of the child targeted, compa Severe and intolerable congestion often requires visits to the rable to a composition or formulation for an adult Which may hospital and treatment. In addition, viral or bacterial infec have double the dosage of the antitussive and analgesic. tions of the sinus passage or other airWay may be passed to [0009] Accordingly, it is desirable to have an administrable healthy persons through symptoms of the congestion. For composition to reduce symptoms of upper respiratory tract example, a cough or sneeZe may convey a bacterium or virus and oral pharyngeal congestion. It is further desirable that the to another person. Thus, upper respiratory tract and oral pha composition be effective in reducing cough, congestion, his ryngeal congestion and its symptoms need to be treated. tamine-stimulated allergy symptoms and related pain. Still [0005] Generally, there are tWo typical approaches to treat further, it is desirable for the composition to contain dosages ing symptoms of the congestion. One approach involves ini suitable for administration to a child as Well as an adult. In tially treating the underlying cause of the symptom. For addition, it is desirable to have the composition in a conve example, a bacterial infection is generally treated by admin nient and pharmaceutically acceptable dosage form. istering an antibiotic to kill the bacteria causing the infection. The second approach involves treating the symptoms them SUMMARY OF THE INVENTION selves, typically in addition to treating the underlying cause, by independently administering one or more medications for [0010] The present invention provides compositions and relief of speci?c symptoms. For example, an antitussive methods for treating upper respiratory and oral pharyngeal agent, commonly referred to as a cough suppressant, has been congestion and related symptoms in a person suffering there typically administered for the treatment or relief of cough. An from. To this end, and in accordance With the principles of the medication, such as and bitar present invention, there is provided a composition of a decon trate, has generally been administered to relieve pain consis gestant, and an antihistamine. Optionally, a composition may tent With the congestion While suppressing a cough. Also include an antitussive, an expectorant and an analgesic. The , such as and , combination of an antitussive, a decongestant, and an antihis have been administered to both children and adults in ?avored tamine in a single composition provides relief of cough, con formulations for reducing mucosal sWelling and draining the gestion in the air passageWays, and common allergy-type US 2013/0210835 A1 Aug. 15,2013

symptoms resulting from exposure to various allergens, in a symptoms. Thus, the present invention encompasses pallia convenient and effective dosage formulation. tive compositions and methods. [0011] The composition is formulated in pharmaceutically [0014] To this end, and in accordance With the principles of acceptable forms such as liquids, pills, capsules, tablets, and the present invention, the compositions include an antitus the like. Suitable capsule forms include, Without limitation, sive, a decongestant, and an antihistamine. Inclusion of an liquid gelatin capsules and enteric -coated capsules. The tablet antihistamine, in combination With an antitussive and a form may be cheWable, may melt or disintegrate in the mouth, decongestant provides relief of histamine-stimulated allergy or may be enteric-coated to provide delayed-release and sus symptoms in addition to relieving other symptoms, such as tained-release characteristics for the composition. In one cough, congestion, sWelling, and pain. These added bene?ts embodiment, the composition is formulated into a liquid. The provide increased ef?cacy and translate into convenience and composition may further include other components, such as cost savings for the patient. conventional excipients including binders, colorants, fra [0015] The present invention provides pharmaceutical grances, and the like, to render the composition more attrac compositions containing an antihistamine along With a tive and suitable for use. decongestant and optionally an analgesic or an antitussive. [0012] By virtue of the foregoing, there is thus provided The compositions of the invention may be administered in compositions and methods for treating upper respiratory and effective dosages for treating nasal congestion symptoms. To oral pharyngeal congestion and related symptoms in effective this end, the pharmaceutical compositions include at least one formulations. These and other bene?ts and advantages of the antihistamine and at least one stimulant. The most potent present invention shall be made apparent from the accompa antihistamines are generally sedating in nature and the seda nying detailed description thereof. tion is reduced or alleviated With the stimulant. The compo sitions are useful for treating allergic reactions and other DETAILED DESCRIPTION OF EXEMPLARY histamine-mediated symptoms, as Well as for providing other EMBODIMENTS physiological effects including, for example, [0013] The present invention provides compositions and effects, analgesic effects, effects, sopori?c methods for treating upper respiratory and oral pharyngeal effects, anti-secretory effects, and combination effects congestion and related symptoms in a patient in need thereof. thereof. By combining a potent, effective antihistamine With The term “upper respiratory and oral pharyngeal congestion” an effective, anti-sedating stimulant, the compositions of the as used herein includes congestion in the oral, pharyngeal, present invention may be administered more safely than prior nasal, and bronchial passages of the upper respiratory tract. It art antihistamine-containing medications utiliZed for the also is intended to include other symptoms, such as cough and same purpose. The present invention also provides methods pain related to allergies, infections, colds, coughs, ?u, viral of use for the pharmaceutical compositions. and bacterial infections, and other common causes for the [0016] Antihistamines suitable for the compositions congestion. Thus, multiple symptoms including congestion include, Without limitation, , cyprohepta may be treated With the compositions of the present invention. dine hydrochloride, brompheneramine, , chlo Treatment includes a reduction in severity or duration, delay ropheniramine, pyrilamine maleate, pyrilamine tannate, in onset, and/or general relief of one or more of these symp acepromaZine, aceprometaZine, , alimemaZine toms. The term is intended to refer to congestion as described tartrate, amoxydramine camsilate, chlorhydrate, herein, as Well as to a Wide range of symptoms related to the antaZoline mesilate, antaZoline phosphate, , aZata congestion or its cause and treatable With the present compo dine dimaleate, hydrochloride, hydro sitions. For example, symptoms related to a common cold or chloride, hydrochloride, tosilate, bro ?u such as cough, fever, and the like, and allergy symptoms maZine hydrochloride, maleate, such as , breakouts, sWelling, and runny nose due to dihydrochloride, bufexamac, maleate acid, external stimulants are treated With the present compositions. cetiedil citrate, dihydrochloride, In addition, symptoms, such as congestion, cough, pain and hydrochloride, maleate, discomfort associated With the congestion, resulting from a hydrochloride, hydrochloride, , bacterial or viral infection, particularly an infection in the fumarate, hexachlorophenate, clemi respiratory tract, are also treated With the present composi Zole penicilline, clemiZole undecylenate, dihy tions. The term “congestion”, as use herein, is intended to drochloride, , clofenetamine hydrochloride, refer to the narroWing of an airWay including the oral, pha hydrochloride, maleate, di ryngeal, nasal and bronchial passages due to ?uid or a solid (acefylline) diphenhydramine, difencloxaZine, dimelaZine substance, such as mucus or phlegm. NarroWing of the airWay hydrochloride, , hydrochlo is often due to sWelling or in?ammation of the mucous mem ride, cimetotiaZine mesilate, diphenhydramine hydrochlo brane lining the passage to result in a partially or fully blocked ride, diphenhydramine mesilate, hydro passage. Severe cases of congestion often cause di?iculties in chloride, diproqualone camsilate, , breathing. Besides allergic reactions, infections, and com succinate, eproZinol dihydrochloride, dimale mon cold and ?u, the symptoms described herein may also be ate, bromhydrate, etybenZatropine hydro due to poor health or a predisposition for the symptom chloride, hydrochloride, hydro through genetic make-up. The terms “treating” and “alleviat chloride, hydrochloride, fenpentadiol, ing”, as used herein With respect to upper respiratory and oral ?unariZine hydrochloride, ?upentixol decanoate, ?upentixol pharyngeal congestion and related symptoms, include any dihydrochloride, hydrochloride, hydroxyZine reduction in severity or duration, of any degree, of the con dihydrochloride, hydroxyZine embonate, indoramine hydro gestion and/or one or more of the related symptoms. The chloride, hydrochloride, ketotifene fumarate, terms also include any delays in onset of and any general hydrochloride, , levomepro relief from the congestion and/or one or more of the related maZine hydrochloride, levomepromaZine embonate, levome US 2013/0210835 A1 Aug. 15,2013

maleate, , hydrochloride, effective dose of the antihistamine, the antitussive, and the maprotiline mesilate, maprotiline resinate, mecloZine hydro decongestant is generally half of an effective dose for a chloride, hydrochloride, fuma patient Without renal dysfunction. rate, mefenidramium metilsulfate, maleate, [0021] While the present composition includes an antitus , methaqualone, hydrochloride, sive, a decongestant, and an antihistamine, the present com hydrochloride, , moxisylyte hydrochlo position is not so limited and may include other components. ride, , hydrochloride, oxa?umaZine These components include conventional excipients, useful disuccinate, , benZilate, oxolamine cit and/or desirable to render the composition suitable or attrac rate, , oxomemaZine hydrochloride, parathiaZ tive for consumption and use. Excipients providing physical ine teoclate, perimetaZine, maleate, phenoxy and aesthetic properties for formulation or delivery of the benZamine hydrochloride, , composition are desirable. For example, With respect to phenyltoloxamine citrate, , , piprete physical properties, ingredients imparting desirable and col dihydrochloride, piZotifene malate, prednaZoline, profe acceptable hardness, disintegration properties, dissolution namine hydrochloride, , promethaZine hydro rate for release of therapeutic components, stability, and siZe to effectively deliver the composition may be included. Dis chloride, promethaZine embonate, promethaZine integrants may be included for the purposes of facilitating the polyvinylbenZene-metacrylate, , , breakup of a tablet after the tablet is administered to the tar‘trate, hydrochloride, thiaZina patient. Examples of disintegrants include, but are not limited mium metilsulfate, hydrochloride, tripelen to, modi?ed or unmodi?ed starches such as cornstarch, potato namine hydrochloride, hydrochloride, and tyma starch, Wheat starch, or sodium cross-carmellos. With respect Zoline hydrochloride, and combinations thereof. to aesthetics, it may be desirable for the composition to con [0017] The antihistamine is included in an amount, per tain additives that appeal to the human senses such as colo dosage of the composition, su?icient to alleviate one or more rants, fragrances, texture modi?ers, and/or ?avorants. Addi histamine-mediated responses in a patient. Effective doses of tionally, many ?avoring agents such as, for example, fruit the antihistamine Will generally vary depending upon the ?avors, or sWeeteners, such as sodium saccharin, confection antihistamine (s) administered. ery sugar, sucrose, xylitol, or combinations thereof, may be [0018] The present composition also includes an antitus included. Additionally, suitable colorants including, for sive. The term “antitussive”, as used herein, is intended to example, red beet poWder, ferric oxide, FD&C dyes, or com include any agent or active ingredient effective for cough binations thereof, may be included in the present composi suppression such as chlophedianol hydrochloride. These also tions. Desirable excipients may also include buffering agents, include, but are not limited to, common opioid surfactants, electrolytes, and thixotropic agents. It should be such as hydrocodone, codeine, , morphine-related understood that these other components should not affect the compounds including diacetylmorphine, , action or mechanism of action of the antitussive, deconges , , , oxyc tant, and/or the antihistamine in the composition. odone, nalmefene, , meperidine, , [0022] Excipients or formulations affecting the release , , , sufentanyl, alfenta properties, mechanisms, and/or rates of the antitussive, the nyl and propoxyphene, and opioid antagonists not structur decongestant, and the antihistamine, from the composition ally-related to morphine, such as nalorphine, naloxone, nal upon oral ingestion may be provided. For example, the com trexone and . In one embodiment, the antitussive position may be formulated such that the release of the anti agent is hydrocodone or a pharmaceutically acceptable salt tussive, the decongestant, and/or the antihistamine or other form thereof, such as hydrocodone bitartrate. active ingredients from the composition is delayed for a [0019] The present composition also includes a deconges period of time or to survive a particular environment. tant. The term “decongestant” as used herein, is intended to [0023] Advantageously, the composition may be formu refer to any agent or ingredient, active for reducing or elimi lated so as to prevent the release of the antitussive, the decon nating congestion of the air passages by Widening the airWay, gestant, and/or the antihistamine in the stomach Where they and/ or by stimulating the release of phlegm and mucus from may likely be acidi?ed, salted out and excreted from the body these passages. Air passages may be Widened by reducing the rather than absorbed into the circulation. For example, the sWelling of the mucous membranes in the passage. Generally, composition may be coated With a coating to improve absorp sympathomimetic drugs have decongestant properties. tion and render the composition more bioavailable than it Examples of suitable decongestants include, Without limita Would otherWise be Without the coating. Enteric coatings or tion, phenylethylamine, epinephrine, norepinephrine, encapsulation-type coatings as knoWn to one skilled in the art , dobutamine, colterol, ethylnorepinephrine, iso are suitable for this purpose. In one embodiment, a table or a proterenol, isoetharine, metaproterenol, terbutaline, met capsule form of the composition is enterically coated so as to araminol, phenylephrine, tyraine, hydroxyamphetamine, provide delayed-release and sustained-release properties to ritodrine, prenalterol, methoxyamine, albuterol, amphet the composition. Sustaining the release of individual active amine, methamphetamine, benZphetamine, , phe ingredients to the body over a period of time prolongs the nylpropanolamine, mephentermine, phentermine, fen?u effective time period of relief from the congestion and related ramine, , diethylpropion, phenmetraZine, symptoms, provided, hoWever, the amount of the ingredient phendimetraZine, , , and pseu in the blood stream is Within the effective therapeutic WindoW doephedrine. for that particular ingredient. Further, preservatives may be [0020] It should be understood that an effective amount of provided to prevent degradation of components in the com the antitussive and the decongestant generally vary With the position or degradation of the composition as a Whole, particular antitussive and decongestant chosen. In addition, thereby improving the stability and prolonging the shelf life an effective amount depends upon many other factors, such as of the composition. knoWn differences in pharmacokinetic parameters (absorp [0024] The composition of the present invention may be tion, distribution and clearance) regardless of the cause. For formulated in a single form. In one embodiment, the form is example, in a patient With a renal dysfunction or disorder, the convenient to sWalloW, and has a generally accepted appear US 2013/0210835 A1 Aug. 15,2013

ance and taste to promote consumption and compliance With composition Will depend upon the form of the composition. a dosing regimen. In accordance With one aspect of the For example, a liquid formulation may be administered to a present invention, the composition is formulated into a dos child in amounts smaller than that administered to an adult. age forrn that may be an ingestible liquid, a pill, a tablet, a Administration Will also depend upon various other factors capsule, a suppository, etc. In accordance With another aspect related to the patient. For example, age, health, Weight, prior of the invention, the composition may be formulated into a medical history, extent and degree of symptoms, and overall parenterally administrable form. It should be understood by medical diagnosis Will generally in?uence the amounts one skilled in the art that certain active agents, such as hydro administered. The composition is generally administered for codone, are typically not parenterally administered, such as alleviating cough, pain, cold and allergy symptoms and also by intra-venous administration. HoWever, other such provides a sedative effect, an analgesic adjuvant effect, an as codeine, morphine, methadone, and fentanyl may be anti-cholinergic affect, and a mild analgesic effect. administered With antihistamine in a non-orally adminis [0029] Formulations of the invention may contain any or all trated formulation. In accordance With a further aspect of the of the folloWing in any combination: Puri?ed Water; Any invention, the present composition may include active ingre combination of permitted API’s added as poWders or as solu dients suitable for sub-lingual administration. In accordance tions, emulsions, suspensions: Chlophedianol Hydrochlo With yet another aspect of the invention, the present compo ride, Pseudoephedrine Hydrochloride, Phenylephrine, or any sition may be administered via mucous membranes of the approved oral nasal decongestant; Dexchlorpheniramine buccal, nasal, rectal cavities, etc. The desired formulation Maleate, Maleate, Brompheniramine may be prepared by a process knoWn in the art of pharmaceu Maleate, ChlorcycliZine Hydrochloride, ThonZylamine tical manufacture. For example, liquid formulations may be Hydrochloride, Pyrilamine Maleate, Tartrate, prepared in the form of a syrup or a suspension. In one or any approved oral antihistamine; or any embodiment, the composition is formulated into an elixir or a approved oral expectorant; Acetaminophen or any approved syrup having a desirable ?avor for easy, trouble-free admin analgesic, antipyretic or anti-in?ammatory; Citric Acid; istration to a child. Sodium Citrate; Propylene Glycol; Flavor; Sodium Saccharin [0025] Solid formulations, such as capsules may be pre Solution (Sodium Saccharin dissolved in Water or any other pared by ?rst blending the antitussive, the decongestant, and solvent); Sorbitol; Glycerin; and Puri?ed Water the antihistamine With other desirable additives and then ?ll [0030] The formulations of the invention may be combined ing capsular materials With the blended mixture using con With any of the folloWing pharmaceutical aids or excipients or ventional ?lling equipment. In one embodiment, the capsular preservatives, added as solutions, suspension, emulsions, or material is a gelatin. The capsule formed may be a liquid directly added as liquids or poWders: Preservatives-including gelatin capsule. Further, Where desired, the capsule may be but not limited to the following: Parabens, BenZoates, Sor coated for added bene?ts. In general, tablets may be formed bates; Arti?cial SWeeteners-including but not limited to the by ?rst blending the components and then either directly folloWing: Sucralose, Saccharin, Acesulfame; SWeeteners compressing the blended components, or granulating the including but not limited to the folloWing: Sucrose, Corn components folloWed by compressing them into a tablet Syrup, High Fructose Corn Syrup, Maltitol, , Dex form. Additional ingredients may be included during com trose, Glucose; Thickeners-including but not limited to the pression Where desired. For example, the granular mixture folloWing: Gums, Mucilages, Xanthan Gum, Guar Gum, Vee may contain one or more lubricants to inhibit sticking during gum, Methylcellulose Derivatives; Buffering Agents-includ compression. Examples of suitable lubricants include, but are ing but not limited to the folloWing: Phosphates, Citrates, not limited to, stearic acid, palmetic acid, stearates, talc, and Sulfates, Carbonates, etc.; and Alcohol Derivatives oils. as Solvents, Preservatives, Flavors; Emulsi?ers; Coloring [0026] The compositions of the invention may also be for Agents, Dyes, Certi?ed Colors; Any and all pharmaceutical mulated as a poWder or sprinkles. excipients [0027] To effectively suppress cough, relieve pain, and [0031] While the present invention has been illustrated by reduce mucus membrane sWelling for reducing congestion the description of embodiments thereof, and While the and other blockage of air passages, the composition of the embodiments have been described in considerable detail, it is present invention includes the antitussive, the decongestant, not intended to restrict or in any Way limit the scope of the and the antihistamine in amounts suitable for treating chil appended claims to such detail. Additional advantages and dren and adults alike. modi?cations Will be readily apparent to those skilled in the [0028] In yet another embodiment of the present invention, art. The invention in its broader aspects is, therefore, not there is provided methods of alleviating symptoms of upper limited to the speci?c details, representative method, and respiratory and oral pharyngeal congestion by orally admin illustrated examples described. Accordingly, departures may istering to a patient in need thereof a single dose of a compo be made from such details Without departing from the scope sition or formulation including an antitussive, a decongestant, or spirit of Applicant’s general inventive concept. and an antihistamine. The patient in need may be a child or an [0032] Examples of the compositions of the invention are adult suffering from the congestion. Administration of the set forth beloW:

ACTIVE 1 ACTIVE 2 ACTIVE 3

Chlophedianol HCl 12.5 mg Pseudoephedrine HCl 30 mg Dexchlorpheniramine Maleate 1 mg Chlophedianol HCl 12.5 mg Pseudoephedrine HCl 30 mg Guaifenesin 100 mg Chlophedianol HCl 12.5 mg Pseudoephedrine HCL 30 mg Guaifenesin 200 mg Chlophedianol HCl 12.5 mg Pseudoephedrine HCl 30 mg Chlorcyclizine 9.375 mg Chlorcyclizine HCl 9.375 mg Pseudoephedrine HCl 30 mg Chlophendianol HCl 25 mg Guaifenesin 200 mg Chlorcyclizine HCl 9.375 mg Pseudoephedrine HCl 30 mg US 2013/0210835 A1 Aug. 15,2013

-c0ntinued

ACTIVE 1 ACTIVE 2 ACTIVE 3

Chlorcyclizine HCl 9.375 mg Pseudoephedrine HCl 30 mg Codeine Phosphate 10 mg Chlorcyclizine HCl 9.375 mg Codeine Phosphate 10 mg Chlophedianol HCl 12.5 mg Dexbrompheniramine 1 mg Phenylephrine HCl 5 mg Chlophedianol HCl 25 mg Pseudoephedrine HCl 60 mg Chloipheniramine Maleate 4 mg Chlorcyclizine HCl 9.375 mg Pseudoephedrine HCl 30 mg Chlophedianol HCl 12.5 mg Chlorcyclizine HCl 9.375 mg Pseudoephedrine HCl 30 mg Dextromethorphan HBr 15 mg Chlophedianol HCl 12.5 mg Guaifenesin 100 mg Phenylephrine HCl 5 mg Thonzylamine HCl 50 mg Codeine Phosphate 10 mg Thonzylamine HCl 50 mg Codeine Phosphate 10 mg Pseudoephedrine HCl 30 mg Chlophedianol HCl 12.5 mg Pseudoephedrine HCl 30 mg Chlophedianol HCl 12.5 mg Dexbrompheniramine 1 mg Phenylephrine HCl 5 mg Chlophedianol HCl 12.5 mg Pseudoephedrine HCl 30 mg Brompheniramine Maleate 2 mg Chlophedianol HCl 12.5 mg Pseudoephedrine HCl 30 mg Chlorcyclizine 9.375 mg Chlophedianol HCl 25 mg Pseudoephedrine HCl 60 mg Chlorcyclizine 18.75 mg Chlophedianol HCl 12.5 mg Phenylephrine HCl 5 mg Chlorcyclizine 9.375 mg Chlophedianol HCL 25 mg Phenylephrine HCl 10 mg Chlorcyclizine 18.75 mg Chlophendianol HCl 25 mg Pseudoephedrine HCl 60 mg Pyrilamine maleate 50 mg Chlophendianol HCl 25 mg Phenylephrine HCl 10 mg Guaifenesin 200 mg Chlophendianol HCl 25 mg Phenylephrine HCl 10 mg Guaifenesin 400 mg Chlophendianol HCl 12.5 mg Guaifenesin 100 mg Chlophendianol HCl 12.5 mg Pseudoephedrine HCl 30 mg Thonzylamine HCl 50 mg Chlophendianol HCl 25 mg Pseudoephedrine HCl 60 mg Thonzylamine HCl 100 mg Chlophendianol HCl 12.5 mg Phenylephrine HCl 5 mg Thonzylamine HCl 50 mg Chlophendianol HCl 25 mg Phenylephrine HCl 10 mg Thonzylamine HCl 100 mg Chlophendianol HCl 25 mg Guaifenesin 400 mg Chlophendianol HCl 25 mg Pseudoephedrine HCl 60 mg Guaifenesin 400 mg Chlorcyclizine HCl 9.375 Phenylephrine HCl 5 mg Chlorcyclizine HCl 18.75 mg Phenylephrine HCl 10 mg Chlorcyclizine HCl 18.75 mg Pseudoephedrine HCl 60 mg Thonzylemine HCl 50 mg Pseudoephedrine HCl 30 mg Thonzylemine HCl 100 mg Pseudoephedrine HCl 60 mg Thonzylemine HCl 50 mg Phenylephrine HCl 5 mg Thonzylemine HCl 100 mg Phenylephrine HCl 10 mg Chlorcyclizine HCl 9.375 mg Pseudoephedrine HCl 30 mg Acetaminophen 325 mg Thonzylemine HCl 50 mg Pseudoephedrine HCl 30 mg Acetaminophen 325 mg Chlorcyclizine HCl 18.75 mg Pseudoephedrine HCl 60 mg Acetaminophen 500 mg Thonzylemine HCl 100 mg Pseudoephedrine HCl 60 mg Acetaminophen 500 mg Chlophendianol HCl 12.5 mg Pseudoephedrine HCl 30 mg Thonzylamine HCl 50 mg Chlophendianol HCl 25 mg Pseudoephedrine HCl 60 mg Thonzylamine HCl 100 mg Chlophendianol HCl 12.5 mg Phenylephrine HCl 5 mg Thonzylamine HCl 50 mg Chlophendianol HCl 25 mg Phenylephrine HCl 10 mg Thonzylamine HCl 100 mg Chlophendianol HCl 12.5 mg Phenylephrine HCl 5 mg Chlorcyclizine HCl 9.375 mg Chlophendianol HCl 25 mg Phenylephrine HCl 10 mg Chlorcyclizine HCl 18.75 mg Chlophendianol HCl 25 mg Pseudoephedrine HCL 60 mg Guaifenesin 200 mg Chlophendianol HCl 25 mg Phenylephrine HCl 10 mg Brompheniramine 4 mg Chlorcyclizine HCl 9.375 mg Codeine Phosphate 10 mg Pseudoephedrine HCl 30 mg Chlorcyclizine HCl 9.375 mg Codeine Phosphate 10 mg Acetaminophen 325 mg Thonzylamine HCl 50 mg Codeine Phosphate 10 mg Pseudoephedrine HCl 30 mg Thonzylamine HCl 50 mg Codeine Phosphate 10 mg Acetaminophen 325 mg Thonzylamine HCl 50 mg Codeine Phosphate 10 mg Phenylephrine HCl 5 mg Chlorcyclizine HCl 9.375 mg Codeine Phosphate 10 mg Phenylephrine HCl 5 mg Chlorcyclizine HCl 9.375 mg Codeine Phosphate 10 mg Phenylephrine HCl 5 mg Thonzylamine HCl 50 mg Codeine Phosphate 10 mg Phenylephrine HCl 5 mg Chlophendianol HCl 12.5 mg Pseudoephedrine HCl 30 mg Chloipheniramine Maleate 2 mg Chlophendianol HCl 12.5 mg Pseudoephedrine HCl 30 mg Dexbrompheniramine Maleate I mg Thonzylamine HCl 50 mg Pseudoephedrine HCl 30 mg Dextromethorphan HBr 15 mg Thonzylamine HCl 50 mg Phenylephrine HCl 5 mg Dextromethorphan HBr 15 mg Chlorcyclizine HCl 9.375 mg Pseudoephedrine HCl 30 mg Dextromethorphan HBr 15 mg Chlorcyclizine HCl 9.375 mg Phenylephrine HCl 5 mg Dextromethorphan HBr 15 mg Chlophedinol HCl 12.5 mg Pseudoephedrine HCl 30 mg Guaifenesin 75 mg Chlorcyclizine HCl 9.375 mg Pseudoephedrine HCl 30 mg Dextromethorphan HBr 15 mg Thonzylamine HCl 50 mg Phenylephrine HCl 5 mg Dextromethorphan HBr 15 mg Chlophendianol HCL 12.5 mg Phenylephrine HCl 5 mg Guaifenesin 200 mg Chlophendianol HCl 12.5 mg Pseudoephedrine HCl 30 mg Pyrilamine Maleate 25 mg Chlophendianol HCl 12.5 mg Phenylephrine HCl 5 mg Pyrilamine Maleate 25 mg Chlophendianol HCl 12.5 mg Pseudoephedrine HCl 30 mg Guaifenesin 100 mg Chlophendianol HCl 25 mg Pseudoephedrine HCl 60 mg Guaifenesin 200 mg Chlophendianol HCl 12.5 mg Phenylephrine HCl 5 mg Guaifenesin 100 mg Chlophendianol HCl 25 mg Phenylephrine HCl 10 mg Guaifenesin 200 mg Chlophendianol HCl 25 mg Pseudoephedrine HCl 60 mg Guaifenesin 400 mg Chlophendianol HCl 25 mg Phenylephrine HCl 10 mg Guaifenesin 400 mg Chlophendianol HCl 12.5 mg Pseudoephedrine HCl 30 mg Guaifenesin 200 mg Chlophendianol HCl 12.5 mg Phenylephrine HCl 5 mg Guaifenesin 200 mg Chlophendianol HCl 12.5 mg Pseudoephedrine HCl 30 mg Doxylamine Succinate 6.25 mg Chlophendianol HCl 12.5 mg Pseudoephedrine HCl 30 mg Doxylamine Succinate 6.25 mg US 2013/0210835 A1 Aug. 15,2013

-continued

ACTIVE 1 ACTIVE 2 ACTIVE 3

Chlophendianol HCl 12.5 mg Phenylephrine HCL 5 mg Doxylamine Succinate 6.25 Chlophendianol HCl 12.5 mg Phenylephrine HCl 5 mg Doxylamine Succinate 6.25 mg Chlophendianol HCl 12.5 mg Pseudoephedrine HCl 30 mg Diphenhydramine HCl 25 mg Chlophendianol HCl 12.5 mg Phenylephrine HCl 5 mg Diphenhydramine HCl 25 mg Chlophendianol HCl 12.5 mg Pseudoephedrine HCl 30 mg Diphenhydramine HCl 25 mg Chlophendianol HCl 12.5 mg Phenylephrine HCl 5 mg Diphenhydramine HCl 25 mg Chlophendianol HCl 12.5 mg Guaifenesin 200 mg Chlophendianol HCl 8.33 mg Brompheniramine 1.33 mg Phenylephrine 33.33 mg Chlorcyclizine HCl 25 mg Pseudoephedrine HCl 60 mg Codeine Phosphate 10 mg Thonzylamine HCl 100 mg Pseudoephedrine HCl 60 mg Codeine Phosphate 10 mg Chlorcyclizine HCl 25 mg Pseudoephedrine HCl 60 mg Chlorcyclizine HCl 25 mg Chlophedianol HCl 25 mg Chlorcyclizine HCl 25 mg Chlophedinol HCl 25 mg Pseudoephedrine HCl 60 mg Chlorcyclizine HCl 25 mg Chlophedianol HCl 12.5 mg Chlophedianol HCl 25 mg Thonzylamine HCl 100 mg Codeine Phosphate 10 mg Thonzylamine HCl 100 mg Pseudoephedrine HCl 60 mg Dextromethorphan HBr 30 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 HCl 25 mg Pseudoephedrine HCl 60 mg Dextromethorphan HBr 30 mg Dextromethorphan HBr 15 mg Chlorcyclizine HCl 9.373 Dextromethorphan HBr 30 mg Chlorcyclizine HCl HBr 18.75 mg Dextromethorphan HBr 15 mg Thonzylamine HCl 50 mg Dextromethorphan HBr 30 mg Thonzylamine HCl 100 mg Chlophedianol HCl 12.5 mg Thonzylamine HCl 50 mg Chlophedianol HCl 12.5 mg Chlorcyclizine HCl 9.375 mg

1. A pharmaceutical composition for alleviating symptoms consisting of Dexchlorpheniramine Maleate, Chlorphe of upper respiratory and oral-pharyngeal congestion in a sub niramine Maleate, dextromethorphan hydrogen bromide, ject, the composition comprising a ?rst active ingredient Pyrilamine maleate, Diphenhydramine HCl, Phenylephrine, selected from the group consisting of chlophedianol hydro Codeine phosphate, Doxylamine Succinate, and Guaifenesin. chloride, chlorcycliZine hydrochloride, thonZylamine hydro 4. The pharmaceutical composition of claim 1, Wherein the chloride and dextromethorphan hydrogen bromide. ?rst active ingredient is present at a range of 9.375 mg to 100 2. The pharmaceutical composition of claim 1, further mg. comprising a second active ingredient selected from the 5. The pharmaceutical composition of claim 2, Wherein the group consisting of Pseudoephedrine Hydrochloride, second active ingredient is present at a range of 1 mg to 100 Guaifenesin, Codeine phosphate, Dexbrompheniramine, mg. Phenylephrine HCl and thonZylamine hydrochloride. 6. The pharmaceutical composition of claim 3, wherein 3. The pharmaceutical composition of claim 2, further third active ingredient is present at a range of 2 mg to 500 mg. comprising a third active ingredient selected from the group * * * * *