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Home , Chlorcyclizine, Etybenzatropine, Fenethazine, Fenpentadiol, Histapyrrodine, Isothipendyl

US 20170020873A1 (19) United States (2) Patent Application Publication (10) Pub. No.: US 2017/0020873 A1 Mitchell (43) Pub. Date: Jan. 26, 2017

(54) PHARMACEUTICAL COMPOSITIONS Publication Classification (71) Applicant:: …~~~ +. *e Inc., Arlington,- (51) A61RInt. Cl. 31/.505 (2006.01) A61 K. 3 1/137 (2006.01) (72) Inventor: Odes W. Mitchell, Arlington, TX (US) A61 K. 3 1/167 (2006.01) A61 K. 3 1/09 (2006.01) - A61 K 37/495 (2006.01) (21)21) Appl. No.:No 15/287,047s A61 K 31/485 (2006.01) 31, 21. A61 K. 3 1/135 (2006.01) (22) Filed: Oct. 6, 2016 A61 K. 3 I/4402 (2006.01) Related U.S. Application- - - Dat (52) U.S. CI. elate pplication Data CPC ...... A61K 31/505 (2013.01); A61K 31/135 (63) Continuation of application No. 14/733,731, filed on (2013.01); A61K 31/137 (2013.01); A61 K Jun. 8, 2015, now Pat. No. 9,463,191, which is a 31/4402 (2013.01); A61K 31/09 (2013.01); continuation of application No. 13/703,584, filed on A61K 31/495 (2013.01); A61K 31/485 Feb. 2, 2013, now Pat. No. 9,050,289, filed as appli- (2013.01); A61K 31/167 (2013.01) cation No. PCT/US2011/040231 on Jun. 13, 2011. (60) Provisional application No. 61/354,053, filed on Jun. (57) ABSTRACT 11, 2010, provisional application No. 61/354,057, A composition of an antitussive, a , or an filed on Jun. 11, 2010, provisional application No. to treat upper respiratory and oral pharyngeal 61/354,061, filed on Jun. 11, 2010. congestion and related symptoms in a patient.

US 2017/0020873 A1 Jan. 26, 2017 chloride, diprodualone camsilate, , , , tyraine, hydroxyamphetamine, succinate, eprozinol dihydrochloride, , , methoxyamine, albuterol, amphet dimaleate, bromhydrate, etybenzatropine amine, , , , phe hydrochloride, hydrochloride, nylpropanolamine, , , fenflu hydrochloride, hydrochloride, , ramine, , diethylpropion, , hydrochloride, decanoate, flupentixol , , , and pseu dihydrochloride, hydrochloride, doephedrine. dihydrochloride, hydroxyzine embonate, indoramine hydro [0020] It should be understood that an effective amount of chloride, hydrochloride, ketotifene fumarate, the antitussive and the decongestant generally vary with the hydrochloride, , levomepro particular antitussive and decongestant chosen. In addition, mazine hydrochloride, levomepromazine embonate, an effective amount depends upon many other factors, such levomepromazine maleate, , hydro as known differences in pharmacokinetic parameters (ab chloride, maprotiline mesilate, maprotiline resinate, sorption, distribution and clearance) regardless of the cause. meclozine hydrochloride, hydrochloride, medi For example, in a patient with a renal dysfunction or foxamine fumarate, mefenidramium metilsulfate, mepyra disorder, the effective dose of the antihistamine, the antitus mine maleate, meduitazine, , sive, and the decongestant is generally half of an effective hydrochloride, hydrochloride, , moxi dose for a patient without renal dysfunction. sylyte hydrochloride, , hydrochlo [0021] While the present composition includes an antitus ride, oxaflumazine disuccinate, , ben sive, a decongestant, and an antihistamine, the present zilate, oxolamine citrate, , oxomemazine composition is not so limited and may include other com hydrochloride, parathiazine teoclate, perimetazine, pheni ponents. These components include conventional excipients, ramine maleate, hydrochloride, phenyl useful and/or desirable to render the composition suitable or toloxamine, citrate, , pipoti attractive for consumption and use. Excipients providing azine, pipretecol dihydrochloride, pizotifene malate, physical and aesthetic properties for formulation or delivery prednazoline, hydrochloride, , of the composition are desirable. For example, with respect promethazine hydrochloride, promethazine embonate, pro to physical properties, ingredients imparting desirable and methazine polyvinylbenzene-metacrylate, , acceptable hardness, disintegration properties, dissolution , tartrate, hydrochlo rate for release of therapeutic components, stability, and size ride, thiazinamium metilsulfate, hydrochlo to effectively deliver the composition may be included. ride, hydrochloride, hydrochlo Disintegrants may be included for the purposes of facilitat ride, and hydrochloride, and combinations ing the breakup of a after the tablet is administered to thereof. the patient. Examples of disintegrants include, but are not [0017] The antihistamine is included in an amount, per limited to, modified or unmodified starches such as corn dosage of the composition, sufficient to alleviate one or more starch, potato starch, wheat starch, or sodium cross-carmel -mediated responses in a patient. Effective doses los. With respect to aesthetics, it may be desirable for the of the antihistamine will generally vary depending upon the composition to contain additives that appeal to the human antihistamine (s) administered. senses such as colorants, fragrances, texture modifiers, and/ [0018] The present composition also includes an antitus or flavorants. Additionally, many flavoring agents such as, sive. The term “antitussive”, as used herein, is intended to for example, fruit flavors, or sweeteners, such as sodium include any agent or active ingredient effective for cough saccharin, confectionery sugar, sucrose, xylitol, or combi suppression such as chlophedianol hydrochloride. These nations thereof, may be included. Additionally, suitable also include, but are not limited to, common analge colorants including, for example, red beet powder, ferric sics such as , , , morphine oxide, FD&C dyes, or combinations thereof, may be related compounds including diacetylmorphine, oxymor included in the present compositions. Desirable excipients phone, , , , may also include buffering agents, surfactants, electrolytes, , nalmefene, , meperidine, pentazo and thixotropic agents. It should be understood that these cine, , , , sufentanyl, other components should not affect the action or mechanism alfentanyl and propoxyphene, and opioid antagonists not of action of the antitussive, decongestant, and/or the anti structurally-related to morphine, such as nalorphine, nalox histamine in the composition. one, maltrexone and . In one embodiment, the anti [0022] Excipients or formulations affecting the release tussive agent is hydrocodone or a pharmaceutically accept properties, mechanisms, and/or rates of the antitussive, the able salt form thereof, such as hydrocodone bitartrate. decongestant, and the antihistamine, from the composition [0019] The present composition also includes a deconges upon oral ingestion may be provided. For example, the tant. The term “decongestant” as used herein, is intended to composition may be formulated such that the release of the refer to any agent or ingredient, active for reducing or antitussive, the decongestant, and/or the antihistamine or eliminating congestion of the air passages by widening the other active ingredients from the composition is delayed for airway, and/or by stimulating the release of phlegm and a period of time or to survive a particular environment. mucus from these passages. Air passages may be widened by [0023] Advantageously, the composition may be formu reducing the swelling of the mucous membranes in the lated so as to prevent the release of the antitussive, the passage. Generally, sympathomimetic have deconges decongestant, and/or the antihistamine in the stomach where tant properties. Examples of suitable include, they may likely be acidified, salted out and excreted from the without limitation, phenylethylamine, epinephrine, norepi body rather than absorbed into the circulation. For example, nephrine, , , , ethylnorepineph the composition may be coated with a coating to improve rine, isoproterenol, isoetharine, metaproterenol, , absorption and render the composition more bioavailable US 2017/0020873 A1 Jan. 26, 2017

than it would otherwise be without the coating. Enteric and other blockage of air passages, the composition of the coatings or encapsulation-type coatings as known to one present invention includes the antitussive, the decongestant, skilled in the art are suitable for this purpose. In one and the antihistamine in amounts suitable for treating chil embodiment, a table or a capsule form of the composition is dren and adults alike. enterically coated so as to provide delayed-release and [0028] In yet another embodiment of the present inven sustained-release properties to the composition. Sustaining tion, there is provided methods of alleviating symptoms of upper respiratory and oral pharyngeal congestion by orally the release of individual active ingredients to the body over administering to a patient in need thereof a single dose of a a period of time prolongs the effective time period of relief composition or formulation including an antitussive, a from the congestion and related symptoms, provided, how decongestant, and an antihistamine. The patient in need may ever, the amount of the ingredient in the blood stream is be a child or an adult suffering from the congestion. Admin within the effective therapeutic window for that particular istration of the composition will depend upon the form of the ingredient. Further, preservatives may be provided to pre composition. For example, a liquid formulation may be vent degradation of components in the composition or administered to a child in amounts smaller than that admin degradation of the composition as a whole, thereby improv istered to an adult. Administration will also depend upon ing the stability and prolonging the shelf life of the com various other factors related to the patient. For example, age, position. health, weight, prior medical history, extent and degree of [0024] The composition of the present invention may be symptoms, and overall medical diagnosis will generally formulated in a single form. In one embodiment, the form is influence the amounts administered. The composition is convenient to swallow, and has a generally accepted appear generally administered for alleviating cough, pain, cold and ance and taste to promote consumption and compliance with symptoms and also provides a effect, an a dosing regimen. In accordance with one aspect of the adjuvant effect, an anti- affect, and a present invention, the composition is formulated into a mild analgesic effect. dosage form that may be an ingestible liquid, a pill, a tablet, [0029] Formulations of the invention may contain any or all of the following in any combination: Purified Water; Any a capsule, a suppository, etc. In accordance with another combination of permitted API’s added as powders or as aspect of the invention, the composition may be formulated solutions, emulsions, suspensions: Chlophedianol Hydro into a parenterally administrable form. It should be under chloride, Hydrochloride, Phenylephrine, stood by one skilled in the art that certain active agents, such or any approved oral nasal decongestant; Dexchlorphemi as hydrocodone, are typically not parenterally administered, ramine Maleate, Maleate, Bromphe such as by intra-venous administration. However, other niramine Maleate, Hydrochloride, such as codeine, morphine, methadone, and fentanyl Thonzylamine Hydrochloride, Pyrilamine Maleate, Phenin may be administered with antihistamine in a non-orally damine Tartrate, or any approved oral antihistamine; Guaife administrated formulation. In accordance with a further nesin or any approved oral expectorant; Acetaminophen or aspect of the invention, the present composition may include any approved analgesic, antipyretic or anti-inflammatory; active ingredients suitable for sub-lingual administration. In Citric Acid, Sodium Citrate; Propylene Glycol; Flavor, accordance with yet another aspect of the invention, the Sodium Saccharin Solution (Sodium Saccharin dissolved in present composition may be administered via mucous mem water or any other solvent); Sorbitol; Glycerin; and Purified branes of the buccal, nasal, rectal cavities, etc. The desired Water formulation may be prepared by a process known in the art [0030] The formulations of the invention may be com of pharmaceutical manufacture. For example, liquid formu bined with any of the following pharmaceutical aids or lations may be prepared in the form of a syrup or a excipients or preservatives, added as solutions, suspension, suspension. In one embodiment, the composition is formu emulsions, or directly added as liquids or powders: Preser vatives—including but not limited to the following: Para lated into an elixir or a syrup having a desirable flavor for bens, Benzoates, Sorbates; Artificial Sweeteners—including easy, trouble-free administration to a child. but not limited to the following: Sucralose, Saccharin, [0025) Solid formulations, such as capsules may be pre Acesulfame; Sweeteners—including but not limited to the pared by first blending the antitussive, the decongestant, and following: Sucrose, Corn Syrup, High Fructose Corn Syrup, the antihistamine with other desirable additives and then Maltitol, , Dextrose, Glucose: Thickeners—includ filling capsular materials with the blended mixture using ing but not limited to the following: Gums, Mucilages, conventional filling equipment. In one embodiment, the Xanthan Gum, Guar Gum, Veegum, Methylcellulose capsular material is a gelatin. The capsule formed may be a Derivatives; Buffering Agents—including but not limited to liquid gelatin capsule. Further, where desired, the capsule the following: Phosphates, Citrates, Sulfates, Carbonates, may be coated for added benefits. In general, tablets may be etc.; and Alcohol Derivatives as Solvents, Preser formed by first blending the components and then either vatives, Flavors; Emulsifiers; Coloring Agents, Dyes, Cer directly compressing the blended components, or granulat tified Colors: Any and all pharmaceutical excipients ing the components followed by compressing them into a [0031] While the present invention has been illustrated by tablet form. Additional ingredients may be included during the description of embodiments thereof, and while the compression where desired. For example, the granular mix embodiments have been described in considerable detail, it ture may contain one or more lubricants to inhibit sticking is not intended to restrict or in any way limit the scope of the during compression. Examples of suitable lubricants appended claims to such detail. Additional advantages and include, but are not limited to, stearic acid, palmetic acid, modifications will be readily apparent to those skilled in the stearates, talc, and oils. art. The invention in its broader aspects is, therefore, not [0026] The compositions of the invention may also be limited to the specific details, representative method, and formulated as a powder or sprinkles. illustrated examples described. Accordingly, departures may [0027] To effectively suppress cough, relieve pain, and be made from such details without departing from the scope reduce mucus membrane swelling for reducing congestion or spirit of Applicant’s general inventive concept.

US 2017/0020873 A1 Jan. 26, 2017 6

-continued

ACTIVE 1 ACTIVE 2 ACTIVE 3 Chlorcyclizine HCl 9.375 mg Phenylephrine HCl 5 mg Dextromethorphan HBr 15 mg Chlophedinol HCl 12.5 mg Pseudoephedrine HC 75 mg 30 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 HC Pseudoephedrine HCl 30 mg Guaifenesin 100 mg 12.5 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 Chlophendianol HCl 12.5 mg Phenylephrine HCl 5 mg Doxylamine Succinate 6.25 mg Chlophendianol HCl 12.5 mg Phenylephrine HCl 5 mg Doxylamine Succinate 6.25 mg Chlophendianol HCl 12.5 mg Pseudoephedrine HCl 30 mg 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 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 HCI 25 mg Pseudoephedrine HCl 60 mg Chlorcyclizine HCI 25 mg Chlophedianol HCI 25 mg Chlorcyclizine HCI 25 mg Chlophedinol HCl 25 mg Pseudoephedrine HCl 60 mg Chlorcyclizine HCl 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 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 HCI 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

What is claimed is: , bromopheniramine maleate, Guaifenesin, Codeine phosphate, and thonzylamine hydrochloride. 1. A pharmaceutical composition for alleviating symp 2. The pharmaceutical composition of claim 1, further toms of upper respiratory and oral-pharyngeal congestion in comprising a third active ingredient selected from the group a subject, the composition comprising: consisting of pyrilamine maleate, Pseudoephedrine Hydro a first active ingredient selected from the group consisting chloride, chlorcyclizine hydrochloride, dexbrompheni of chlophedianol hydrochloride, chlorcyclizine hydro ramine maleate, diphenhydramine hydrochloride, diphenhy dramine citrate, chlorpheniramine maleate, chloride, phenylephrine hydrochloride, dextrometho maleate, doxylamine succinate, tripro rphan hydrobromide and thonzylamine hydrochloride; lidine hydrochloride, dextromethorphan hydrobromide, bro and mopheniramine maleate, Guaifenesin, Codeine phosphate, a second active ingredient selected from the group con and thonzylamine hydrochloride. sisting of pyrilamine maleate, Pseudoephedrine Hydro 3. The pharmaceutical composition of claim 1, wherein chloride, chlorcyclizine hydrochloride, dexbrompheni the first active ingredient is present at a range of 9.375 mg ramine maleate, diphenhydramine hydrochloride, to 100 mg. diphenhydramine citrate, chlorpheniramine maleate, 4. The pharmaceutical composition of claim 1, wherein dexchlorpheniramine maleate, doxylamine succinate, the second active ingredient is present at a range of 1 mg to triprolidine hydrochloride, dextromethorphan hydro 100 mg. US 2017/0020873 A1 Jan. 26, 2017

5. The pharmaceutical composition of claim 2, wherein third active ingredient is present at a range of 1 mg to 500 mg.