US 200701.41 147A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2007/0141147 A1 Heil et al. (43) Pub. Date: Jun. 21, 2007

(54) SEQUENTIAL RELEASE Publication Classification PHARMACEUTICAL FORMULATIONS (51) Int. Cl. (75) Inventors: Matthew F. Heil, Duluth, GA A6II 3/55 (2006.01) (US); Glynn Wilson, Duluth, GA A63L/485 (2006.01) (US s s A6IR 9/22 (2006.01) A63/37 (2006.01) Correspondence Address: AOIN 31/08 (2006.01) PATREAL PABST (52) U.S. Cl...... 424/468; 514/282: 514/304: 514/649; PABST PATENT GROUP LLP 514/217.05: 514/731 400 COLONY SQUARE, SUITE 1200, 1201 s PEACHTREE STREET ATLANTA, GA 30361 (57) ABSTRACT A mixed-release tablet or capsule formulation including (73) Assignee: Auriga Laboratories, Inc. vehicles for the delivery of a plurality of drugs in various combinations of immediate release, extended release, and/or (21) Appl. No.: 11/461,238 delayed release modes over a predetermined time period 1-1. have been developed, which provide for controlled release (22) Filed: Jul. 31, 2006 not just of the drugs, but controlled release that is designed O O to create more effective coordination between the drugs Related U.S. Application Data being delivered. The drugs can be any medically and/or (60) Provisional application No. 60/752,057, filed on Dec. physiologically appropriate combination of drugs and active 21, 2005, provisional application No. 60/761,766, ingredients, preferably decongestant drugs, antihistamines, filed on Jan. 25, 2006, provisional application No. expectorants, antitussives, cough Suppressants, and drying 60/791,408, filed on Apr. 13, 2006. agents. US 2007/01.41 147 A1 Jun. 21, 2007

SEQUENTIAL RELEASE meta to the aliphatic side chain. The meta position affords PHARMACEUTICAL FORMULATIONS optimal activity. Phenylephrine (neo-synephrine) replaced an older preparation, Synephrine, in which the hydroxyl was CROSS-REFERENCE TO RELATED in the para position. Phenylephrine hydrochloride is avail APPLICATIONS able in the form of the levorotatory isomer, which is a white, odorless, non-hygroscopic, crystalline compound possess 0001 Priority is claimed to U.S. application Nos. 60/752, ing a bitter taste. Phenylephrine hydrochloride has a melting 057, filed Dec. 21, 2005; 60/761,766 filed Jan. 25, 2006; and point of 140-145° C. and is freely soluble in water and 60/791,408 filed Apr. 13, 2006 alcohol. Decongestant compounds in the form of their free bases as well as their pharmaceutically acceptable salts, e.g., FIELD OF THE INVENTION hydrochloride, citrate, maleate, tannate, etc., are used. Expectorants, such as guaifenesin, change a dry, unproduc 0002 The present invention provides a mixed-release tive cough to one that is more productive and less frequent. formulation that contains a plurality of active therapeutic Guaifenesin, known chemically as 3-(2-methoxyphenoxy)- agents and provides continuous immediate and/or extended 1.2-propanediol, is a crystalline powder, which is soluble in dosing and delayed dosing for a predetermined time period, water and alcohol. It is indicated in the USP Drug informa up to at least 12 hours. tion as an expectorant for the symptomatic relief of cough due to colds and minor upper respiratory infections. BACKGROUND OF THE INVENTION 0004 Phenylephrine may be present in amounts of 0003. Existing methods for the treatment of a variety of between about 15 and about 60 milligrams per capsule, conditions involve the administration of more than one preferably from about 5 milligrams to about 30 milligrams active agent using formulations that allow for immediate as per capsule, with half or less of that amount used in a well as controlled release. The drug delivery profiles of such pediatric form of the formulation. Delsym DM(R) (Novartis) formulations are simple, usually involving the immediate is an example of a Sustained-release dextromethorphan release of an active ingredient, followed by the sustained composition. The Sustained-release characteristics of the release of the same ingredient, or a different active ingre composition are achieved by the use of Small particles of an dient, delayed for a certain period of time. However, many ion-exchange resin bound to the dextromethorphan that of these formulations fail to take advantage of combining delay release of the drug in the gastrointestinal tract. How multiple controlled, delayed, or immediate release profiles ever, the bioavailability of dextromethorphan is relatively within a single preparation other than just combinations of low due to the strong bond between residual amounts of immediate and delayed release. In particular, present meth dextromethorphan and the ion exchange resin. The total ods for the treatment of cold or allergic rhinitis symptoms percentage of dextromethorphan released from dex rely upon a wide variety of agents, most principally anti tromethorphan-ion exchange resin complexes is incomplete, histamines (e.g., Chlorpheniramine), expectorants e.g., and under certain in vitro conditions it has been observed guaifenesin), decongestants (e.g., pseudoephedrine or phe that even after a twelve hour period of time, about 20% of nylephrine) and drying agents (e.g., the antisecretory drug dextromethorphan remains bound to the ion exchange resin. methScopolamine). Dextromethorphan is antitussive agent 0005 Examples of the preparation of sustained release used in many over-the-counter cold medications. It has an formulations of individual cough-cold medicines include opioid-like structure but, being a D-isomer, it does not U.S. Pat. No. 6,416,786 to Mulaye (sustained release for possess the analgesic or addictiveness of opioids. It acts mulation of guaifenesin); U.S. Patent Application Publica centrally to relieve cough, similar to opioids. It is active tion No. 20050152967 by Tengler et al. (mixed release against dry cough and does not exhibit significant expecto formulations of an expectorant for immediate release and a rant properties for productive cough. MethScopolamine decongestant for extended release); U.S. Pat. No. 6,955,821 nitrate is an anticholinergic and is a derivative of Scopola to Davis et al. (Sustained release formulation of guaifenesin mine. It possess the peripheral actions of the belladonna and at least one other drug, wherein guaifenesin is formu alkaloids, but does not exhibit the central actions because of lated for both immediate and extended release); and U.S. its inability to cross the blood-brain barrier. In cough-cold Pat. No. 6,372,252 Blume et al. (sustained release guaifen preparations, it is most often used for its anti-secretory effect esin formulations where guaifenesin is formulated for both on the upper respiratory system. However, methScopolamine immediate and extended release). has a relatively short plasma half-lie and needs an extended 0006 While some mixed release compositions have been release formulation to provide symptomatic relief over described, as discussed above, there is still a need in the art extended periods of time. Chlorpheniramine, often admin to create controlled release pharmaceutical formulations istered as the maleate salt, is a short-acting antihistamine with better sequential release characteristics that orchestrate (H1) compound that also has a short plasma half-life. Chlo the Symphony of symptomatic release agents to better fit the rpheniramine also requires an extended release formulation needs of patients Suffering from a cold, or those experienc to provide extended symptomatic relief in cough-cold for ing cold like symptoms in terms of decongestant, expecto mulations. Phenylephrine is an alpha agonist that acts as a rant and drowsiness characteristics. decongestant in cough-cold formulations. Phenylephrine 0007. Therefore it is an object of the present invention to also requires a longer acting formulation. Phenylephrine provide a formulation with a tighter control of different drug hydrochloride, also known as (S)-3-hydroxy-alpha(me release than what is achieved with an immediate release thylamino) methylbenzene methanol hydrochloride, is an Sustained release formulation. orally effective nasal decongestant. Phenylephrine is a syn 0008. It is a further object of the invention to provide a thetic, optically active sympathomimetic amine that has one formulation including an expectorant for immediate and hydroxyl group on the benzene ring. The hydroxyl group is extended release, and a cough suppressant for delayed and US 2007/01.41 147 A1 Jun. 21, 2007

extended release, wherein the release profiles of the ingre such that up to 50% of the antitussive active drug is released dients are orchestrated to better co-ordinate the production in immediate fashion over the first 1 to 4 hours, followed by and clearance of mucus and cough suppression. Sustained release of the antitussive drug, such that up to 100% of the antitussive active drug is released between 4 to SUMMARY OF THE INVENTION 12 hours. In another embodiment, the pharmaceutical for mulations include an expectorant for immediate and 0009. A mixed-release tablet or capsule formulation extended release, and a cough suppressant for delayed and including vehicles for the delivery of a plurality of drugs in extended release, wherein the release profiles of the ingre various combinations of immediate release, extended dients are orchestrated to better co-ordinate the production release, and/or delayed release modes over a predetermined and clearance of mucus and cough suppression. time period have been developed which provide for con 0011. The pharmaceutical formulation may include a trolled release not only of the drugs, but controlled release combination of the anti-tussive, anti-histamine and drying that is designed to create more effective coordination agent; a combination of the decongestant and drying agent; between the drugs being delivered. The drugs can be any a combination of the decongestant and cough suppressant; a medically and/or physiologically appropriate combination combination of the expectorant and cough suppressant; or a of active agents and active ingredients, preferably decon combination of the expectorant and anti-tussive in a capsule, gestants, antihistamines, expectorants, antitussives, cough tablet, oral rapid dissolving tablet, softget, gelcap, film, gum, Suppressants, and drying agents. Representative deconges pastille, lozenge, disk, or wafer form. The antitussives, tants include phenylephrine (bitartrate, tannate, HBr, or HCl antihistamines, decongestants, expectorants, drying agents salts), phenylpropanolamine (HCl), pseudoephedrine (HCl). or combinations thereof may be formulated as immediate and combinations thereof. Representative antihistamines release granules, delayed release granules, extended release include chlorpheniramine (maleate), brompheniramine granules; or optionally as a free drug depending on the (maleate), dexchloropheniramine (maleate), dexbromophe desired pharmacological effect. The formulations may niramine (maleate), triprolidine (HCl), diphenhydramine include effective amounts of each of dextromethorphan (HCl), doxylamine (succinate), tripelennamine (HCl). (HBr), chlorpheniramine (maleate), methScopolamine (ni cyproheptatine (HCl), bromodiphenydramine (HCl), phen trate), pseudoephedrine (HCl), phenylephrine (HCl). indamine (tartarate), pyrilamine (maleate, tamate), azatadine guaifenesin, and hydrocodone (bitartrate). The anti-tussive (maleate), and combinations thereof. Representative expec active drug can be dextromethorphan in a form such as a torants include guaifenesin, terpin hydrate, (glyceryl guai Sustained release granule, a sustained release matrix, or acolate), potassium (iodide, citrate), potassium guaiacolsul combinations thereof, and the anti-histamine active drug can fonate, and combinations thereof. Representative antitussive be chlorpheniramine in a form Such as a Sustained release agents include caramiphen (edisylate), dextromethorphan bead, a Sustained release matrix, or combinations thereof. (HBr), codeine (phosphate, sulfate), hydrocodone (bitar The drying agent active drug can be methScopolamine in the trate), and combinations thereof. form of a delayed release granule. The decongestant can be 0010 Appropriate vehicles for the delivery of the drugs pseudoephedrine in the form of a mixture of an immediate may be liquid, gel, semisolid, paste, or Solid. More specifi release bead, an immediate release matrix, and a Sustained cally, these vehicles may be microparticles, for example, release bead, a Sustained release matrix, or combinations microspheres or other micronized forms, granules, beads, or thereof. resins. In various embodiments, the tablet or capsule phar 0012. In one embodiment, the tablet or capsule pharma maceutical formulation includes one or more of the follow ceutical formulation can include: ing granules: immediate-release granules, delayed release 0013 (a) an anti-tussive active drug within a granule granules, extended release granules; and optionally free drug matrix packaged for extended release of over 90% of or a plurality of different drugs, wherein each formulation of the active drug released substantially linearly over up to granules include individual beads containing soluble and/or at least a 12 hour period of time; insoluble polymers and an active drug or a plurality of drugs. 0014 (b) an anti-histamine active drug packaged for In another embodiment, the formulations include a decon extended release of over 90% of the active drug gestant for immediate and extended release, an antihista released substantially linearly over up to a least a 12 mine for extended release, and a drying agent for delayed hour period of time; and and extended release, wherein the release profiles of the 0015 (c) a drying agent active drug packaged for ingredients are controlled to orchestrate the effectiveness of delayed and extended release of over 90% of the active their pharmacological action. For example, the formulation drug released substantially linearly over a period of 8 may comprise an expectorant for immediate and extended hours following an initial delay of release of from about release, wherein over 90% of the drug is released substan tially linearly over a 12 hour period of time, and a cough 2 to about 4 hours. Suppressant for delayed and extended release, wherein over 0016. In another embodiments, the pharmaceutical com 90% of the drug is released between 4 to 12 hours, wherein position can include: the release profiles of the ingredients are orchestrated to 0017 (a) an immediate release decongestant active co-ordinate the production and clearance of mucus and drug packaged immediate release of over 60-80% of cough Suppression. In one embodiment, the pharmaceutical the active drug within from about 90 minutes to about composition includes an extended release expectorant active 120 minutes following dosing: drug packaged for extended release of over 90% of the 0.018 (b) an extended release decongestant active drug expectorant active drug released substantially linearly over packaged for extended release of over 90% of the up to at least a 12 hour period of time; and an antitussive active drug released substantially linearly over up to a active drug packaged for immediate and Sustained release, 12 hour period of time; and US 2007/01.41 147 A1 Jun. 21, 2007

0019 (c) a drying agent active drug packaged for includes one or more excipients. Alternatively, a sequential delayed and extended release of over 90% of the active release tablet formulation is made by compressing a mixture drug released substantially linearly over up to at least of excipients and a mixture of granules into a tablet, wherein an 8 hour period following an initial delay of release of each type of granule includes individually an extended from about 2 to about 4 hours. release anti-tussive, an extended release anti-histamine and 0020. In another embodiment, the pharmaceutical com a drying agent in a delayed release form. The mixture of position can include: excipients may further include free active drug. The anti 0021 (a) an immediate release expectorant active drug tussive agent can be dextromethorphan, the anti-histamine packaged for immediate release of over 60-80% of the can be chlorpheniramine, and the drying agent can be active drug within from about 90 minutes to about 120 methScopolamine. minutes following dosing: 0035 Another method for making a sequential-release 0022 (b) an extended release expectorant active drug formulation includes loading a mixture of different types of packaged for extended release of over 90% of the granules and an excipient formulation into a capsule, active drug released substantially linearly over up to at wherein the mixture of granules includes an active drug least a 12 hour period of time; within a polymer matrix and wherein the active drug mixture 0023 (c) optionally, a drying agent active drug pack includes an immediate release decongestant, an extended age for delayed and extended release of over 90% of the release decongestant, and a drying agent in a delayed and active drug released substantially linearly over up to at extended release form. The anti-tussive agent can be dex least an 8 hour period following an initial delay of tromethorphan, the anti-histamine can be chlorpheniramine, release of from about 2 to about 4 hours; and and the drying agent can be methScopolamine. 0024 (d) optionally, a cough Suppressant active drug 0036 Still another method for making a sequential-re packaged for delayed and extended release of over 90% lease formulation includes loading a mixture of different of the active drug released substantially linearly over types of granules into a capsule, wherein each type of up to at least an 8 hour period following an initial delay granule includes individually an extended release expecto of release of from about 2 to about 4 hours. rant, and a cough suppressant in a delayed and extended 0025. In another embodiment, pharmaceutical composi release form, and wherein the capsule includes one or more tion can include: excipients. 0026 (a) an immediate release expectorant active drug 0037. In one embodiment, the expectorant can be packaged for immediate release of over 60-80% of the guaifenesin and the cough suppressant can be hydrocodone. active drug within from about 90 minutes to about 120 In one embodiment of a formulation of hydrocodone and minutes following dosing: guaifenesin, up to 20% of the hydrocodone can be released 0027 (b) an extended release expectorant active drug in a sustained fashion over the first 1 to 4 hours, followed by packaged for extended release of over 90% of the the sustained release of up to 100% of the remaining amount active drug released substantially linearly over up to at of the hydrocodone between 4 to 12 hours. least a 12 hour period of time; 0038. In another formulation of hydrocodone and 0028 (c) optionally, a drying agent active drug pack guaifenesin, the release of hydrocodone is achieved in two aged for delayed and extended release of over 90% of sequential immediate release pulses, where between 0 to 5 the active drug released Substantially linearly over up to mg of hydrocodone is released between 1 to 4 hours, and 5 at least an 8 hour period following an initial delay of to 10 mg of the hydrocodone is released after 4 to 6 hours. release of from about 2 to about 4 hours; and In yet another formulation of hydrocodone and guaifenesin, 0029 (d) optionally, an antitussive active drug pack 20-35% of guaifenesin is released between 0 to 2 hours, aged for delayed and extended release of over 90% of 35-65% is released between 2 to 4 hours, and 65-90% is the active drug released Substantially linearly over up to released between 4 to 8 hours. In another formulation of at least an 8 hour period following an initial delay of hydrocodone and guaifenesin, up to 50% of the hydroc release of from about 2 to about 4 hours. odone (0-5 mg) is released between 1 to 4 hours, and 5 to 10 0030. In variations of these embodiments, the immediate mg of the hydrocodone is released in a Sustained fashion release forms of the drugs are optional. between 4 to 12 hours. In this specific formulation guaifen 0031. In a specific embodiment, the pharmaceutical com esin is released in a Sustained fashion between 1-12 hours. position can include: 0032 (a) an extended release form of guaifenesin DETAILED DESCRIPTION OF THE packaged for extended release of over 90% of the INVENTION active drug released substantially linearly over up to at least a 12 hour period of time; 0039 Definitions 0033 (c) hydrocodone formulated for delayed and 0040. As used herein, “solid pharmaceutical composi extended release of over 90% of the active drug tions' include, but are not limited to, oral dosage forms such released substantially linearly over up to at least an 8 as tablets, capsules, caplets, gelcaps, wafers, films, gums, hour period following an initial delay of release of from pastilles, lozenges, matrices, disks. Such compositions are about 2 to about 4 hours. predominantly solid Such that appropriate dosages are 0034. A method for providing a sequential-release for achieved by the subject without the need for a separate mulation has also been developed, wherein different types of measuring device. Such as a spoon, measuring cup or granules are loaded into a capsule, wherein each type of dropper. Such compositions can include liquid constituents granule includes individually an extended release anti-tus or compositions, including gels and slurries. sive, an extended release antihistamine and a drying agent in 0041 As used herein “delayed release” means that about a delayed release form, and wherein the capsule further 90% or more of the active therapeutic agent administered US 2007/01.41 147 A1 Jun. 21, 2007

and contained within the formulation, for example within and drying effects better fitted with the patient’s needs. granules, is delayed for about 1 to 4 hours, more precisely, Patients who have experienced an exposure to an allergen 2 to 4 hours, after administration, from being released from benefit from a rapid release of the antihistamine chlorphe the granules and available to systemic exposure. niramine but, one removed from the presence the allergen, 0042. As used herein “sustained release' or “extended better benefit from the sustained release of a decongestant release” means that about 90% or more of the active combined with the longer term drying effects of methsco therapeutic agent administered and contained within the polamine, the gradual controlled release of which is delayed formulation, for example, within granules, is released from 2-4 hours after dosing. By this time, the immediately the granules and available to systemic exposure over there released chlorpheniramine effects are declining and are period of time where release is sustained and released over Supplemented by a Sustained drying effect provided by a Substantially linear rate. methScopolamine and a decongestant effect provided by 0043. As used herein “immediate release” means that at phenylephrine. This example also illustrates ways in which about 90% or more of the active therapeutic agent admin the combination of delayed, controlled and immediate istered and contained within the formulation, for example, release actives can be blended to avoid side effects found in within granules, is release within a period of 1 to 3 hours some combinations of less skillfully regulated blends of after administration and available to systemic exposure. actives. Chlorpheniramine and methScopolamine are highly Immediate release may also be defined functionally as the effective in their own regard. For example, while both release of over about 80 to 90 percent 15 (%) of the active chlorpheniramine and methScopolamine are highly effec ingredient within about 60, 90, 100 or 120 minutes or less. tive, both have anticholinergic activity which, when com 0044 As used herein, a “pulse' relates to a release of the bined as in a simple controlled release preparation contain active therapeutic agent at a contemplated point in time. For ing both actives, causes excessive and uncomfortable drying example, a pulse can be delayed, but once the point in time in some patients. However, by combining a release profile is reached following administration, the active therapeutic for chlorpheniramine that sequentially provides relief from agent can be released immediately. Pulses can be sequential. the different actives, a therapeutic is created that is more For example, a first immediate release pulse can occur at effective in addressing both the short term and long term time point X, which is followed later by a second immediate therapeutic needs of patients while avoiding unpleasant side release pulse at time point Y. Although commencement of effects resulting from less precise delivery profiles. the second immediate release pulse is delayed in comparison 0048 A. Pharmaceutically Active Compounds to the commencement and possibly the completion of first 0049. The drugs may be any medically and/or physiologi time pulse, the release of the second will be immediate cally appropriate combination of drugs and active ingredi following the delay. ents described in United States Pharmacopoeia (“USP), the 0045. The term “about in the context of numerical Physician's Desk Reference (“PDRW), and the Food and values and ranges refers to values or ranges that approximate Drug Administration (“FDA) publication, “Approved Drug or are close to the recited values or ranges such that the Products with Therapeutic Equivalence Evaluations, also method or composition can perform as intended, as is known as the “Orange Book.” The drugs can be any medi apparent from the teachings contained herein. Thus, this cally and/or physiologically appropriate combination of term encompasses values beyond those simply resulting drugs and active ingredients, preferably decongestant drugs, from systematic error. Typically, the term “about” means antihistamines, expectorants, antitussives, cough Suppres plus or minus ten percent. sants, and drying agents. Representative decongestant active I. Formulation drugs include phenylephrine (bitartrate, tannate, HBr, HCl). 0046. The formulations are based on the recognition that phenylpropanolamine (HCl), pseudoephedrine (HCl), and patients and physicians are looking to simplify the number combinations thereof. Representative antihistamine active of doses that a patient takes and to improve the timing of drug include chlorpheniramine (maleate), brompheniramine onset of drug action consistent with improving patient (maleate), dexchloropheniramine (maleate), dexbromophe compliance and outcomes. The underlying rational is the use niramine (maleate), triprolidine (HCl), diphenhydramine of combinations of drugs in a single therapeutic preparation, (HCl), doxylamine (Succinate) tripelennamine (HCl), cypro where each active agent or drug, or groups of drugs is heptatine (HCl), bromodiphenhydramine (HCl), phenin formulated in a specific release profile so as to provide in damine (tartarate), pyrilamine (maleate, tamate), azatadine combination with the other actives agents to provide a (maleate), and combinations thereof. Representative expec sequence of complementary therapeutic actions. The thera torant active drug include guaifenesin, terpin hydrate, (glyc peutic utility of the formulation is a result of orchestrating eryl guaiacolate), potassium (iodide, citrate), potassium the overall utility of the therapeutic preparation over time. guaiacolsulfonate, and combinations thereof. Representative For example, a therapeutic formulation that is formulated to antitussive active drug include caramiphen (edisylate), dex be taken in the early evening provides an immediate dose of tromethorphan (HBr), codeine (phosphate, sulfate), hydro guaifenesin that can assist in breaking up mucus and initi codone (bitartrate), and combinations thereof. Representa ating a productive cough. As the guaifenesin action tive cough suppressants include benzonatate, decreases, the drying and decongestant activities of a selec bromodiphenhydramine, brompheniramine, buclizine, tively delayed and controlled release methScopolamine and carbinoxamine, chlorpheniramine, clemastine, codeine, phenylephrine provides longer term drying and deconges cyclizine, dexchloropheniramine, dextromethorphan, dihy tant activity and which is less likely to interfere with the drocodeine, dimenhydrinate, diphenhydramine, doxy user's sleep. lamine, homatropine, hydrocodone, meclizine, pheniramine, 0047 Methscopolamine and phenylephrine can delayed phenyltoloxamine, pyrilamine, trimethobenzamide, triproli for about 2-4 hours after administration and only released so dine. Representative drying agents include methScopola as to provide a sequence of mucolytic and then decongestant mine, Scopolamine, meclizine, trimethobenzamide, dimen US 2007/01.41 147 A1 Jun. 21, 2007 hydrinate, cyclizine, pheniramine, buclizine, 0056. Optional pharmaceutically acceptable excipients chlorpheniramine, diphenhydramine, homatropine, carbi present in the drug-containing tablets, beads, granules or noxamine, clemastine, brompheniramine, and doxylamine. particles include, but are not limited to, diluents, binders, 0050 Effective Dosages are known. lubricants, disintegrants, colorants, stabilizers, and Surfac B. Excipients tantS. 0051 0057 Diluents, also termed “fillers.” are typically neces 0052 Appropriate vehicles for the delivery of the drugs sary to increase the bulk of a solid dosage form so that a may be liquid, gel, semisolid, paste, or Solid. More specifi practical size is provided for compression of tablets or cally, these vehicles may be microparticles, for example, formation of beads and granules. Suitable diluents include, microspheres or other micronized forms, granules, beads, or but are not limited to, dicalcium phosphate dihydrate, cal resins. In various embodiments, the tablet or capsule phar cium Sulfate, lactose. Sucrose, mannitol, Sorbitol, cellulose, maceutical formulation includes one or more of the follow microcrystalline cellulose, kaolin, sodium chloride, dry ing granules: immediate-release granules, delayed release starch, hydrolyzed starches, pregelatinized starch, silicone granules, extended release granules; and optionally free drug dioxide, titanium oxide, magnesium aluminum silicate and or a plurality of different drugs, wherein each formulation of powder Sugar. granules includes individual beads containing soluble and/or 0.058 Binders are used to impart cohesive qualities to a insoluble polymers and an active drug or a plurality of drugs. Solid dosage formulation, and thus ensure that a tablet or In another embodiment, the formulations include a decon bead or granule remains intact after the formation of the gestant for immediate and extended release, an anti-hista dosage forms. Suitable binder materials include, but are not mine for extended release, and a drying agent for delayed limited to, starch, pregelatinized starch, gelatin, Sugars (in and extended release, wherein the release profiles of the cluding Sucrose, glucose, dextrose, lactose and Sorbitol), ingredients are controlled to orchestrate the effectiveness of polyethylene glycol, waxes, natural and synthetic gums such their pharmacological action. In another embodiment, the as acacia, tragacanth, Sodium alginate, cellulose, including inventive pharmaceutical formulations include an expecto hydroxypropylmethyl cellulose, hydroxypropylcellulose, rant for immediate and extended release, and a cough ethylcellulose, and Veegum, and synthetic polymers such as Suppressant for delayed and extended release, wherein the acrylic acid and methacrylic acid copolymers, methacrylic release profiles of the ingredients are orchestrated to better acid copolymers, methyl methacrylate copolymers, ami coordinate the production and clearance of mucus and cough noalkyl methacrylate copolymers, polyacrylic acid/poly Suppression. methacrylic acid and polyvinylpyrrolidone. 0053 Formulations are prepared using a pharmaceuti 0059 Lubricants are used to facilitate tablet manufacture. cally acceptable “carrier composed of materials that are Examples of suitable lubricants include, but are not limited considered safe and effective and may be administered to an to, magnesium Stearate, calcium Stearate, Stearic acid, glyc individual without causing undesirable biological side erol behenate, polyethylene glycol, talc, and mineral oil. effects or unwanted interactions. The “carrier is all com 0060 Disintegrants are used to facilitate dosage form ponents present in the pharmaceutical formulation other than disintegration or “breakup” after administration, and gener the active ingredient or ingredients. The term “carrier' ally include, but are not limited to, starch, Sodium starch includes, but is not limited to, diluents, binders, lubricants, glycolate, Sodium carboxymethyl starch, Sodium carboxym desintegrators, fillers, and coating compositions. ethylcellulose, hydroxypropyl cellulose, pregelatinized 0054 “Carrier also includes all components of the coat starch, clays, cellulose, alginine, gums or cross linked poly ing composition which may include plasticizers, pigments, mers, such as cross-linked polyvinylpyrrolidone (Polyplas colorants, stabilizing agents, and glidants. The delayed doneR XL from GAF Chemical Corp). release dosage formulation may be prepared as described in 0061 Stabilizers are used to inhibit or retard drug decom references such as “Pharmaceutical dosage form tablets'. position reactions which include, by way of example, oxi eds. Liberman et. al. (New York, Marcel Dekker, Inc., 1989), dative reactions. “Remington The science and practice of pharmacy”. 20th 0062 Surfactants may bee anionic, cationic, amphoteric ed., Lippincott Williams & Wilkins, Baltimore, Md., 2000, or nonionic Surface active agents. Suitable anionic Surfac and "Pharmaceutical dosage forms and drug delivery sys tants include, but are not limited to, those containing car tems'. 6. Sup.th Edition, Ansel et al., (Media, Pa...: Williams boxylate, Sulfonate and Sulfate ions. Examples of anionic and Wilkins, 1995) which provides information on carriers, Surfactants include Sodium, potassium, ammonium of long material, equipment and process for preparing tablets and chain alkyl Sulfonates and alkyl aryl Sulfonates such as capsules and delayed release dosage forms of tablets, cap Sodium dodecylbenzene Sulfonate; dialkyl sodium sulfo Suc Sules, and granules. cinates, such as Sodium dodecylbenzene Sulfonate; dialkyl 0055 Examples of suitable coating materials include, but Sodium SulfoSuccinates. Such as sodium bis-(2-ethylth are not limited to, cellulose polymers such as cellulose ioxyl)-Sulfo Succinate; and alkyl Sulfates Such as sodium acetate phthalate, hydroxypropyl cellulose, hydroxypropyl lauryl Sulfate. Cationic Surfactants include, but are not methylcellulose, hydroxypropyl methylcellulose phthalate limited to, quaternary ammonium compounds Such as ben and hydroxypropyl methylcellulose acetate Succinate; poly Zalkonium chloride, benzethonium chloride, cetrimonium vinyl acetate phthalate, acrylic acid polymers and copoly bromide, Stearyl dimethylbenzyl ammonium chloride, poly mers, and methacrylic resins that are commercially available oxyethylene and coconut amine. Examples of nonionic under the trade name Eudragit R. (Roth Pharma, Westerstadt, Surfactants include ethylene glycol monostearate, propylene Germany), Zein, shellac, and polysaccharides. Additionally, glycol myristate, glyceryl monostearate, glyceryl Stearate, the coating material may contain conventional carriers such polyglyceryl-4-oleate, Sorbitan acylate. Sucrose acylate, as plasticizers, pigments, colorants, glidants, stabilization PEG-150 laurate, PEG-400 monolaurate, polyoxyethylene agents, pore formers and Surfactants. monolaurate, polysorbates, polyoxyethylene octylphe US 2007/01.41 147 A1 Jun. 21, 2007

nylether, PEG-1000 cetyl ether, polyoxyethylene tridecyl 0067 Extended release tablets containing wax materials ether, polypropylene glycol butyl ether, Poloxamer R 401, are generally prepared using methods known in the art Such Stearoyl monoisopropanolamide, and polyoxyethylene as a direct blend method, a congealing method, and an hydrogenated tallow amide. Examples of amphoteric Sur aqueous dispersion method. In a congealing method, the factants include Sodium N-dodecyl-3-alanine, sodium drug is mixed with a wax material and either spray-con N-lauryl-B-iminodipropionate, myristoamphoacetate, lauryl gealed or congealed and screened and processed. betaine and lauryl sulfobetaine. 0063. If desired, the tablets, beads granules or particles Delayed Release Dosage Forms may also contain minor amount of nontoxic auxiliary Sub stances such as wetting or emulsifying agents, dyes, pH 0068 Delayed release formulations are created by coat buffering agents, and preservatives. ing a solid dosage form with a film of polymer which is insoluble in the acid environment of the stomach, and soluble in the neutral environment of small intestines. Extended Release Dosage Forms 0069. The delayed release dosage units can be prepared, for example, by coating a drug or a drug-containing com 0064. The extended release formulations are generally position with a selected coating material. The drug-contain prepared as diffusion or osmotic systems, for example, as ing composition may be, e.g., a tablet for incorporation into described in “Remington The Science and practice of a capsule, a tablet for use as an inner core in a "coated core pharmacy” (20th ed., Lippincott Williams & Wilkins, Bal dosage form, or a plurality of drug-containing beads, par timore, Md., 2000). A diffusion system typically consists of ticles or granules, for incorporation into either a tablet or two types of devices, reservoir and matrix, and is well capsule. Preferred coating materials include bioerodible, known and described in the art. The matrix devices are gradually hydrolyzable, gradually water-soluble, and/or generally prepared by compressing the drug with a slowly enzymatically degradable polymers, and may be conven dissolving polymer carrier into a tablet form. The three tional “enteric' polymers. Enteric polymers, as will be major types of materials used in the preparation of matrix appreciated by those skilled in the art, become soluble in the devices are insoluble plastics, hydrophilic polymers, and higher pH environment of the lower gastrointestinal tract or fatty compounds. Plastic matrices include, but not limited to, slowly erode as the dosage form passes through the gas methyl acrylate-methyl methacrylate, polyvinyl chloride, trointestinal tract, while enzymatically degradable polymers and polyethylene, Hydrophilic polymers include, but are not are degraded by bacterial enzymes present in the lower limited to, methylcellulose, hydroxypropylcellulose, gastrointestinal tract, particularly in the colon. Suitable hydroxypropylmethylcellulose, sodium carboxymethylcel coating materials for effecting delayed release include, but lulose, and Carbopol.R. 934, polyethylene oxides. Fatty com are not limited to, cellulosic polymers such as hydroxypro pounds include, but are not limited to, various waxes such as pyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellu a carnauba wax and glyceryl tristearate. lose, hydroxypropyl methyl cellulose, hydroxypropyl 0065. Alternatively, extended release formulations can be methyl cellulose acetate Succinate, hydroxypropylmethyl prepared using osmotic systems or by applying a semi cellulose phthalate, methylcellulose, ethyl cellulose, cellu permeable coating to the dosage form. In the latter case, the lose acetate, cellulose acetate phthalate, cellulose acetate desired drug release profile can be achieved by combining trimellitate and carboxymethylcellulose sodium; acrylic acid low permeable and high permeable coating materials in polymers and copolymers, preferably formed from acrylic Suitable proportion. acid, methacrylic acid, methyl acrylate, ethyl acrylate, 0066 Extended release tablets containing hydrophilic methyl methacrylate and/or ethyl methacrylate, and other polymers are prepared by techniques commonly known in methacrylic resins that are commercially available under the the art Such as direct compression, wet granulation, or dry tradename Eudragit(R) (Rohm Pharma; Westerstadt, Ger granulation processes. Their formulations usually incorpo many), including EudragitR) L30D-55 and L100-55 (soluble rate polymers, diluents, binders, and lubricants as well as the at pH 5.5 and above), Eudragit(R) L-100 (soluble at pH 6.0 active pharmaceutical ingredient. The usual diluents include and above), Eudragit(R) S (soluble at pH 7.0 and above, as a inert powdered Substances such as any of many different result of a higher degree of esterification), and Eudragits(R) kinds of starch, powdered cellulose, especially crystalline NE, RL and RS (water-insoluble polymers having different and microcrystalline cellulose, Sugars such as fructose, degrees of permeability and expandability); Vinyl polymers mannitol and Sucrose, grain flours and similar edible pow and copolymers such as polyvinyl pyrrolidone, vinyl acetate, ders. Typical diluents include, for example, various types of vinylacetate phthalate, vinylacetate crotonic acid copolymer, starch, lactose, mannitol, kaolin, calcium phosphate or Sul and ethylene-vinyl acetate copolymer; enzymatically fate, inorganic slats such as Sodium chloride and powdered degradable polymers such as azo polymers, pectin, chitosan, sugar. Powdered cellulose derivatives are also useful. Typi amylose and guar gum, Zein and shellac. Combinations of cal tablet binders include Substances such as starch, gelatin different coating materials may also be used. Multi-layer and Sugars such as lactose, fructose, and glucose. Natural coatings using different polymers may also be applied. and synthetic gums, including acacia, alginates, methylcel 0070 The preferred coating weights for particular coat lulose, and polyvinylpyrrolidone can also be used. Polyeth ing materials may be readily determined by those skilled in ylene glycol, hydrophilic polymers, ethylcellulose and the art of evaluating individual release profiles for tablets, waxes can also serve as binders. A lubricant is necessary in beads and granules prepared with different quantities of a tablet formulation to prevent the tablet and punches from various coating materials. It is the combination of materials, sticking in the die. The lubricant is chosen from such method and form of application that produce the desired slippery Solids as talc, magnesium and calcium Stearate, release characteristics, which one can determine only from Stearic acid and hydrogenated vegetable oils. the clinical studies. US 2007/01.41 147 A1 Jun. 21, 2007

0071. The coating composition may include conventional covalently bound functional groups, wherein the functional additives, such as plasticizers, pigments, colorants, stabiliz groups are ionic or capable of being ionized under the ing agents, glidants, etc. A plasticizer is normally present to appropriate conditions of pH. The organic matrix may be reduce the fragility of the coating, and will generally rep synthetic (e.g., polymers or copolymers of acrylic acid, resent about 10 wt.% to 50 wt.% relative to the dry weight methacrylic acid, Sulfonated Styrene, Sulfonated divinylben of the polymer. Examples of typical plasticizer include Zene), or partially synthetic (e.g., modified cellulose and polyethylene glycol, propylene glycol, triacetin, dimethyl dextrans). The inorganic matirX can also be, for example, phthalate, diethyl phthalate, dibutyl phthalate, dibutyl seba silica gel modified by the addition of ionic groups. The cate, triethyl citrate, tributyl citrate, triethyl acetyl citrate, covalently bound ionic groups may be strongly acidic (e.g., castor oil and acetylated monoglycerides. A stabilizing agent Sulfonic acid), weakly acidic (e.g., carboxylic acid), strongly is preferably used to stabilize particles i the dispersion. basic (e.g., quaternary ammonium), weakly basic (e.g., Typical stabilizing agents are nonionic emulsifiers. Such as primary mine), or a combination of acidic and basic groups. Sorbitan esters, polysorbates and polyvinylpyrrolidone. In general, those types of ion exchangers suitable for use in Glidants are recommended to reduce Sticking effects during ion exchange chromatography and for Such applications as film formation and drying, and will generally represent deionization of water are suitable for use in the granule approximately 25 wt.% to 100 wt.% of the polymer weight component. Such ion exchangers are described by H. F. in the coating solution. One effective glidant is talc. Other Walton in “Principles of Ion Exchange” (pp. 312-343), glidants such as magnesium Stearate and glycerol incorporated by reference herein. Useful ion exchange resins monostearates may also be used. Pigments such as titanium generally have exchange capacities below about 6 mil dioxide may also be use. Small quantities of an anti-foaming liequivalents per gram (med/g) and preferably below about agent, Such as a silicone (e.g., simethicone), may also be 5.5 med/g. The granule ion-exchange resin is cross-lined added to the coating composition. with a crosslinking agent selected from difunctional com 0072. As will be appreciated by those skilled in the art pounds capable of cross-linking polystyrenes. The cross and as described in the pertinent texts and literature, a linking agent can be a divinyl or polyvinyl compound. The number of methods are available for preparing drug-con cross-linking agent can be divinylbenzene. The resin is taining tablets, beads, granules or particles that provide a cross-linked to an extent of about 3 to about 20%, preferably variety of drug release profiles. Such methods include, but about 4 to about 1696, more preferably about 6 to about are not limited to, the following: coating a drug or drug lo%, and most preferably about 8% by weight based on the containing composition with an appropriate coating mate total resin. Representative granule resins include Amber rial, typically although not necessarily incorporating a poly lite(R) IRP-69 (Rohm and Haas) and Dow XYS(R)-40010.00 meric material, increasing drug particle size, placing the (Dow Chemical Company). Both are sulfonated. polymers drug within a matrix, and forming complexes of the drug composed of polystyrene cross-linked with 8% of divinyl with a suitable complexing agent. benzene, with an ion exchange capacity of about 4.5 to 5.5 0073. The delayed release dosage units may be coated med./g of dry resin (Ht-form). Their essential difference is in with the delayed release polymer coating using conventional physical form. Amberlite(R) 1W-69 consists of irregularly techniques, e.g., using a conventional coating pan, an airless shaped particles with a size range of 47 to 149 um, produced spray technique, fluidized bed coating equipment (with or by 15 milling the parent, large-sized spheres of Amberlite(R) without a Wurster insert), or the like. For detailed informa IRP-120. The Dow XYS8-40010.00 produce consists of tion concerning materials, equipment and processes for spherical particles with a size range of 45 to 150 um. preparing tablets and delayed release dosage forms, see Another useful exchange resin, Dow XYSR-40013.00, is a Pharmaceutical Dosage Forms: Tablets, eds. Lieberman et polymer composed of polystyrene cross-linked with 8% of al. (New York: Marcel Dekker, Inc., 1989), and Ansel et al., divinylbenzene and functionalized with a quaternary ammo Pharmaceutical Dosage Forms and Drug Delivery Systems, nium group; its exchange capacity is normally within the 6.sup.th Ed. (Media, Pa...: Williams & Wilkins, 1995). range of approximately 3 to 4 med/g of dry resin. (0076 U.S. Pat. Nos. 2,990,332 to Keating and 4.221,778 Sustained Release Formulations to Raghunathan, describe adsorption techniques of active drug agents onto ion exchange resin particles to form the 0074 Sustained release matrices are prepared from mix drug-resin complex. Briefly, the drug is mixed with an tures of soluble polymers such as ethylcellulose, cellulose aqueous Suspension of the resin, and the complex is then acetate, vinyl acetatelvinyl chloride copolymer, acrylate washed and dried. Adsorption of drug onto the resin may be methacrylate copolymers, polyethylene oxide, hydroxypro detected by measuring a change in the pH of the reaction pyl methylcellulose, carageenan, alginic acid and salts medium, or by measuring a change in concentration of thereof, hydroxyethyl cellulose, hydroxypropyl cellulose, Sodium or drug. Binding of drug to resin can be accom karaya gum, acacia gum, tragacanth gum, locust bean gum, plished according to four general reactions. In the case of a guar gum, Sodium carboxymethyl cellulose, methyl cellu basic drug, these are: (a) resin (Na-form) plus drug (salt lose, beeswax, carnauba wax, cetyl alcohol, hydrogenated form); (b) resin ma-form) plus drug (as free base); (c) resin vegetable oils, Stearyl alcohol; and combinations thereof. (H-form) plus drug (salt form); and (d) resin (H-form) plus Carbohydrate particles (non-pareils) can be used as inert drug (as free base). All of these reactions except (d) have cores or carriers in capsule and tablet formulations and are cationic by-products, by completing with the cationic drug coated by active ingredients. These particles are usually for binding sites on the resin, reduce the amount of drug spherical and contain sucrose (62.5%-91.5%) and starch. bound at equilibrium. For basic drugs, stoichiometric bind 0075 Ion exchange resins suitable for use in granule ing of drug to resin is accomplished only through reaction components are water-insoluble and consist of a pharma (d). Four analogous binding reactions can be carried out for ceutically inert organic or inorganic matrix containing binding an acidic drug to an anion exchange resin. These are: US 2007/01.41 147 A1 Jun. 21, 2007

(a) resin (el-form) plus drug (salt form); (b) resin (C1-form) number of conventional techniques, typically starting from plus drug (as free acid; (c) resin (OH-form) plus drug (salt a fluid dispersion. For example, a typical method for pre form); and (d) resin (OH-form) plus drug (as free acid). For paring drug-containing beads involves dispersing or dissolv acidic drugs, Stoichiometric binding of drug to resin is ing the active agent in a coating Suspension or solution accomplished only through reaction (d). The binding may be containing pharmaceutical excipients such as polyvinylpyr performed, for example, as a batch or column process, as is rolidone, methylcellulose, talc, metallic Stearates, silicone known in the art. The drug-resin complex formed is col dioxide, plasticizers or the like. The admixture is used to lected and washed with ethanol and/or water to insure coat a bead core such as a Sugar sphere (or so-called removal of any unbound drug. The complexes are usually “non-pareil) having a size of approximately 60 to 20 mesh. air-dried in trays at room or elevated temperature. The I0083. An alternative procedure for preparing drug beads drug-resin complex has a ratio of active drug(s) to resin of is by blending drug with one or more pharmaceutically about 1:3 to about 3:1, preferably about 1:2 to about 2:1, acceptable excipients, such as microcrystalline cellulose, most preferably about 1:1 (by weight). lactose, cellulose, polyvinyl pyrrolidone, talc, magnesium 0077 C. Formulations Stearate, a disintegrant, etc., extruding the blend, spheroniz 0078. The devices with different drug release mecha ing the extrudate, drying and optionally coating to form the nisms described above can be combined in a final dosage immediate release beads. form comprising single or multiple units. Examples of I0084 Active pharmaceutical ingredients (API's) can be multiple units include multilayer tablets, capsules containing processed by agglomeration, air Suspension drying, balling, tablets, beads, granules, etc. An immediate release portion coacervation, coating, comminution, compression, cryoplel can be added to the extended release system by means of letization, encapsulation, extrusion, wet granulation, dry either applying an immediate release layer up top of the granulation, homogenization, inclusion complexation, lyo extended release core using coating or compression process philization, melting, microencapsulation, mixing, molding, or in a multiple unit System Such as a capsule containing pan coating, Solvent dehydration, Sonication, spheroniza extended and immediate release beads. tion, spray drying or other processes known in the art to form 0079. In one embodiment, a tablet or capsule pharma granules. ceutical formulation includes an anti-tussive agent in an I0085. In a wet granulation method, the at least one immediate release form, and anti-histamine in an extended pharmaceutically active agent and other ingredients are release form and a drying agent in a delayed and extended granulated with a granulating fluid (e.g., isopropyl alcohol, release form. ethyl alcohol, and water) in a planetary mixer, high shear 0080. In another embodiment, the composition includes a mixer, or fluidized bed granulator. Binding agents may be decongestant packed for immediate release; a decongestant contained in the granulating fluid, or may be in the dry mix. packed for extended release, and a drying agent packed for The wet granules are dried in an oven or fluidized bed dryer, delayed and Sustained release, wherein the decongestant and then sieved through a suitable screen to obtain free provides immediate decongestant relief followed by long flowing granules. The resulting granules are blended with a acting decongestant activity, wherein the release of the Suitable lubricant and glidant, and the lubricated granules drying agent is delayed to allow initial decongestion fol are compressed into tablets on a rotary press using appro lowed by long-acting drying agent activity. priate tooling. If desired, a coating can be applied onto a 0081. In another embodiment, a time-release dex rotary press using appropriate tooling. If desired, a coating tromethorphan and a timed release chlorpheniramine are can be applied onto the compressed tablets. formulated to provide maximum effective release over up to I0086 Typical excipients used in these methods include at least 12 hours or more using a combination of polymers bulking agents, disintegrating agents, anti-adherents and in the bead matrix or coat. The drying agent methScopola glidants, lubricants, and binding agents. Bulking agents mine is formulated to provide a 2 to 4 hour delay of release include, but are not limited to, microcrystalline cellulose followed by maximum effective release between 4 to 8 hours (e.g., Avicel(RQ, FMC Corp.; Emcocel(RQ, Mendell Inc.), using a combination of polymers in the bead matrix and mannitol. Xylitol, dicalcium phosphate (e.g., Emcompress.(R), coating materials such as pH sensitive polymers or shellac. JRS Pharma) calcium sulfate (e.g., Compactrol R, JRS Pharma) starches, lactose. Sucrose (Dipac, Amstar, and Methods of Manufacture Nutab, Ingredient Technology), dextrose, sorbitol, cellulose powder (Elcema, Degussa, and Solka Floc, JRS Pharma). 0082. A preferred method of preparing an extended The bulking agent may be present in the pharmaceutical release tablet is by compressing a drug-containing blend, composition in an amount of from about 5 wt.% to about 90 e.g., blend of granules, prepared using a direct blend, wt.% preferably from about 10 wt.% to about 50 wt.%. wet-granulation, or dry-granulation process. Extended Disintegrating agents may be included in the pharmaceutical release tablets may also be molded rather than compressed, formulation and include, for example, microcrystalline cel starting with a moist material containing a suitable water lulose, starches, crospovidone (e.g., Polyplasdone XLR, soluble lubricant. However, tablets are preferably manufac International Specialty Products.), sodium starch glycolate tured using compression rather than molding. A preferred (Explotab(R, JRS Pharma), and crosscarmellose sodium method for forming extended release drug-containing blend (e.g., Ac-Di-Sol R, FMC Corp.). The disintegrating agent is to mix drug particles directly with one or more excipients may be present in the composition in an amount of from Such as diluents (or fillers), binders, disintegrants, lubricants, about 0.5 wt.% to about 30 wt.%, preferably from about 1 glidants, and colorants. As an alternative to direct blending, wt.% to about 20 wt.%. Antiadherants and glidants may be a drug-containing blend may be prepared by using wet used in the pharmaceutical composition include, for granulation or dry-granulation processes. Beads containing example, talc, corn starch, silicon dioxide, Sodium lauryl the active agent may also be prepared by any one of a Sulfate, and metallic Stearates. The antiadherent or glidant US 2007/01.41 147 A1 Jun. 21, 2007 may be present in the pharmaceutical formulation in an expectorant. The mean particle size of the granule ion amount of from about 0.2 wt. '% to about 15 wt. '%, exchange resins is within the range of about 100 to about preferably from about 0.5 wt.% to about 5 wt.%. 300 pm. 0087. Examples of lubricants used in the excipient mix 0090. In another embodiment pharmaceutical combina tions include extended release granules of anti-histamines, ture include magnesium Stearate, calcium Stearate, sodium decongestants, are mixed with delayed and Sustained release Stearate, Stearic acid, Sodium Stearyl fumarate, hydrogenated formulations of drying agents and compressed into rapid cotton seed oil (sterotex), talc, and waxes, including but not dissolving oral tablets. The tablet can further include a limited to, beeswax, carnauba wax, cetyl alcohol, glyceryl binder to permit particles of the porous, plastic Substance Stearate, glyceryl palmitate, glyceryl behenate, hydroge and the water penetration enhancer to adhere to each other nated vegetable oils, and Stearyl alcohol. The lubricant may Sufficiently to prevent particle segregation and to increase be present in an amount of from about 0.2 wt.% to about 20 granule adherence at the low pressure used to form the wt.%, preferably from about 0.5 wt.% to about 5 wt.%. tablet. The binder can include from about 1% to about 90% Binding agents include, for example, polyvinyl pyrrolidone, of the tablet by weight. For example, the binder can be starch, methylcellulose, hydroxypropyl methylcellulose, fructose or mannose. The tablet can further include at least carboxymethyl cellulose, Sucrose solution, dextrose solu one additional ingredient selected from the group consisting tion, acacia, tragacanth and locust bean gum. The binding of a surfactant, Superdisintegrant, Superporous hydrogel agent may be present in the composition in an amount of particle, effervescent agent, lubricant, flavoring agent, a from about 0.2 wt.% to about 10 wt.%, preferably from coloring agent and combinations thereof. Some formulations about 0.5 wt.% to about 5 wt.%. Granules (coated or use effervescent couples as their disintegrant, while others uncoated) containing active agents are combined with use a combination of disintegrants. U.S. Pat. No. 6,596.311 excipients and compressed into a table formulation. describes different types of non-effervescent disintegrants. 0088. Extended release and delayed release formulations 0091. The formulation can include three active drugs, may be prepared and delivered so that release is accom each within its own granule composition or within the tablet plished in some generally predictable location in the lower or capsule matrix, wherein the active drugs are an anti intestinal tract more distal than would have accomplished if tussive, an antihistamine, and a drying agent. For example, there had been no delayed release alterations. A method for from about 5% to about 20% of the total active anti-tussive delay of release is a polymeric coating on each granule is contained within the polymeric material and from about intended for extended or delayed release in a more distal 80% to about 95% is packaged within the extended release portion of the gastrointestinal tract. Any coatings should be granules polymeric material. For example, from about 5% to applied in Sufficient thickness Such that the entire coating about 20% of the drying agent is release over the first four does not dissolve in the gastrointestinal fluids at pH below hours after dosing and from about 80% to about 95 percent about 5, but does dissolve at pH 5 and above. It is expected is released in the period from 4 hours to 24 hours after that any anionic polymer exhibiting a pH-dependent solu dosing. For example, from about 5% to about 20% of the bility profile can be used as an enteric coating in the practice total active antihistamine is contained within the rapid of the present invention to achieve delivery to the lower dissolve polymeric material and from about 80% to about gastrointestinal tract. Polymers and compatible mixtures 95% is packaged within the extended release granules thereof may be used to provide the coating for the delayed polymeric material. The active anti-tussive can be dex or the extended release of active ingredients. By way of an tromethorphan. The active antihistamine can be chlorphe example, the Sustained release of dextromethorphan, chlor niramine. The drying agent can be methScopolamine. The pheniramine, and methScopolamine, over up to at least a 12 decongestant can be phenylephrine or pseudoephedrine. hour or more period, was achieved through formulation in a matrix of hydroxyproply methylcellulose (Methocel(R) EXAMPLE 1. K100M Premium USP Powder), dicalcium phosphate dihy drate, crosscannellose Sodium, silicon dioxide, microcrys Sustained Release Table of Dextromethorphan. talline cellulose pH 102 and magnesium Stearate. Sustained 0092. This example provides a sustained release tablet of release granules of methScopolamine, prepared from the dextromethorphan, chlorpheniramine and methScopolamine. same excipients can be coated with pH sensitive polymers The tablet was prepared by direct compression of the that degrade in the lower G1 tract, (e.g., Eudragit R. L. ingredients listed in Table 1: Eudragit(R) S. Aquot AS-HF, and ethylcellulose) so that release of active is delayed for 2 to 4 hours until the granule TABLE 1. reached the distal ileum colon. The length of the day is controlled by the thickness of coating (amount). Granules TABLET FORMULATION can also be coated with shellac. The resulting mixture of granules and excipients can be either compressed into a Component Weight Tablet (mg) tablet or filled into a capsule. Dextromethorphan hydrobromide 30.60 Chlorpheniramine maleate 8.16 0089. In one embodiment, the compositions include Methscopolamine nitrate 2.55 drug-resin complexes having two or three active ingredients. Dicalcium phosphate dehydrate OSO In another embodiment, the invention also provides phar Croscarmellose sodium (powder) 22.50 maceutical compositions including the drug-resins in com Methocel(R) (K10OM Premium USP powder) 37.50 Silicon Dioxide S.OO bination with Suitable pharmaceutically acceptable excipi Microcrystalline cellulose PHIO2 380.69 ents, and optionally at least one of an antihistamine, Magnesium Stearate 12.SO sympathomimetic drug (nasal decongestant, bronchodila tor), analgesic, antiinflammatory, cough suppressant and/or US 2007/01.41 147 A1 Jun. 21, 2007

0093. This formulation achieved a sustained release of all containing chlorpheniramine maleate (8 mg) and phenyle actives approximately linearly over a 12 hour period. In phrine HCl (20 mg), and methScopolamine nitrate (2.5 mg). formulation that require a delayed release of methScopola Chlorpheniramine maleate, 90K Kollidon(R) and Cab-o-sil mine, Sustained release granules of methScopolamine, pre were mixed and then coated with SURELEASE(R) to form pared using excipients shown in Table 1, were coated (10-65% by weight), with the water insoluble and pH the first Sustained release granules. Delayed release (second) sensitive polymers, Eudragit(R) RS or Eudragit(R) RL, or granules having methScopolamine as the active drug and combination thereof, using a Wurster Fluidized Bed pro containing 90F Kollidon, Cab-041 were coated with cess. Coated granules of methScopolamine were blended Eudragit(R) RS or Eudragit(R) RL or combinations thereof. with the other actives and either directly compressed into The coated granules achieved a delayed release of methsco tablets or filled into capsules. polamine for about 2-4 hours compared to the other actives. Mixtures of first sustained release and second delayed EXAMPLE 2 release granules were combined with a fast-dissolving Sustained Release Beads of Guaifenesin excipient systems, (F-Melt, Fuji Chemical Industry) or 0094 Sustained release beads of guaifenesin were pre PharmaburstTM (SPI Pharmaceuticals), and then directly pared. Briefly, guaifenesin was first granulated with 3% 90F compressed into tablets. These tablets dissolved in the oral Kollidon(R) and 0.2% Cab-o-Sil, dried and the mixture passed through a 60 20 mesh screen to collect 200 um cavity within 30 seconds. Typically, the final rapid dissolve particles. The particles were then placed in a Surster Fluid formulation contained fast-dissolving excipients (-40-70% ized Bed coating machine and coated with a latex dispersio by weight), Sustained and delayed release granules contain of ethyl cellulose (SURELEASE(R), Colorcon). Coated gran ing actives (-30-60% by weight) and magnesium Stearate ules were air dried. The ingredients of the coated granules (-0.4%) are listed in Table 2 below:

TABLE 2 EXAMPLE 4

Component % (by weight) Sustained Release Beads or Granules Guaifenesin 58.7 SURELEASE (R) 39.4 0097. A capsule was prepared containing sustained 90F Kollidon (R) 1.8 release beads or granules of chlorpheniramine maleate and Cab-o-Sil 1.O phenylephrine HC1. Delayed release beads or granules of methScopolamine nitrate were added to the capsule formu Dissolution tests were then carried out on the granules of this lation. example using a standard USP 23NF Drug Release Appa Formulation 1: ratus filled with 999 ml of the dissolution medium in the vessel and equilibrated to 37° C.-0.5° C. The paddles were 0098. Chlorpheniramine maleate (30 mg), phenylephrine set to rotate at 60 RPM. 1 G of granules was added to each HCl (15 mg), methScopolamine nitrate (1.25-2.5 mg), non vessel. The percent dissolution was determined by HPLC pareil beads (Sugar Spheres NF of 16-18 mesh cut), Shellac, and the results shown in Table 3 below: Eudragit(R) S, Eudragit(R) L. Chlorpheniramine maleate and TABLE 3 phenylephrine HCl were individually transferred to a coat Time (h) ing pan and added to non-pareil beads using Shellac, and allowed to roll and cure for 6 hours before sustained release 51.2 73.6 coating was added. The beads were coated with different 86.1 amounts of Shellac (ratio of bed mix: Shellac of 1.5:1-2:1) 93.3 97.0 to achieve a Sustained release of active for up to 12 hours. 99.3 After coating the coated beads were at 40° C. 100.1 0099 Beads loaded with methscopolamine were coated together with a first layer of Shellac and then coated again Additional coating with SURELEASE(R) prolonged the sustained release of guaifenesin to about 12 hours. by an outer layer(s) of a mixture of Eudragit(R) S and 0095. In formulations that require a delayed release of Eudragit R. L. This results in a delayed release of active drugs hydrocodone, the drug plus the Sustained release excipients, for 2 to 4 hours followed by a sustained release. shown in Table 2, were granulated with 3% 90F Kollidon Formulation 2: and 0.2% Cab-o-Sil, sized and then dried. The particles were 0100 Chlorpheniramine maleate (30 mg), phenylephrine then coated (-10-65% by weight) with water insoluble HCl (15 mg), methscopolamine nitrate (1.25-2.5 mg), dical polymers Eudragit(R) RS or Eudragit R. RL or combinations cium phosphate dehydrate, croscnnellose sodium, Metho thereof, using a Wurster Fluidized Bed coating machine. These granules were then blended with guaifenesin granules cel(R) K100M premium USP powder, ProsolvCDR (silicil and directly compressed into tablets. ized HPMC; JRS Pharma), magnesium stearate, Eudragit(R) S, Eudragit R L are provided in a formulation to first form EXAMPLE 3 mini-tabs (Mini Tab Press, SMI) and then load the mixture Oral Rapid Dissolving Tablets of mini-tabs into capsules. Chlorpheniramine maleate and 0096. This example illustrates the making of an oral rapid phenylephrine HCl are blended with the other excipients and dissolving tablets prepared from Sustained release granules compressed into mini-tabs (2 mm in length). Methscopola US 2007/01.41 147 A1 Jun. 21, 2007 mine nitrate is separately blended with excipients including, of either guaifenesin or the hydrocodone bitartrate. The croscarmellose sodium, Methocel(R) K10OM, magnesium tablet is formulated so as to release guaifenesin and hydro stearate, and Prosolv(R), and the blend is compressed into 5 codone over a period of 8 to 12 hours after ingestion. The mini-tabs. The mini-tabs are coated with Eudragit(R) S and formulation includes the following standard excipients: Eudragit(R) L to give a delayed release. Mini-tabs (2 mm in 0.104 Dicalcium phosphate dihydrate length) are loaded into capsules. Prosolv(a) is used for the 0105 Croscarmellose sodium compression of mini-tabs. 01.06 Methocel(R) K10OM Formulation 3: Chlorpheniramine Delayed and Sustained 01.07 Silicon Dioxide Release Tablets 0108 Microcrystalline cellulose PH 102 (sustained 0101 Chlorpheniramine maleate (30 mg), phenylephrine release component) HCl (15 mg), methscopolamine nitrate (1.25-2.5 mg), dical 0.109 Magnesium stearate cium phosphate dehydrate (0.5 mg), croScarmellose sodium 0110. The sustained release core is coated with an imme (22.5 mg), Methocel(R) K100M premium USP powder (37.5 diate release film containing 5 mg cough Suppressant (hy mg), silicon dioxide (5 mg), microcrystalline cellulose drocodone bitartrate) by processes readily known to those PH102 (380 mg), magnesium stearate (12.5 mg), Eudragit(R) skilled in the art. S, Eudragit(R) L, are used in a formulation of tablets having both delayed release and Sustained release characteristics. EXAMPLE 7 Chlorpheniramine maleate and phenylephrine HCl are blended with the above excipients. Methscopolamine nitrate Sustained Release Granules is separately blended with the above excipients and granu 0111. This example provides a matrix tablet of sustained lated. After drying, the methScopolamine nitrate granules are release granules, in the form of bead manufactured by direct coated with Eudragit R. S/L using a Wurster Fluidized Bed compression that provides a release profile of Sustained coating machine. The resulting coated methScopolamine release of guaifenesin and hydrocodone over a period of 8 to granules are introduced into the chlorpheniramine maleate? 12 hours after ingestion. The formulations are designed Such phenylephrine HCl blend and compressed into tablets. The that 10 to 20% of the hydrocodone is released within the first resulting formulation can achieve a Sustained release of 4 hours after ingestion, and 80 to 90% of the hydrocodone chlorpheniramine maleate and phenylephrine HCl over a 12 is released between 4 to 12 hours after ingestion. There are hours period and a Sustained release of methScopolamine no separate immediate release guaifenesin components in nitrate after an initial 2-4 hours delay. the formulations. Variation in the properties of the guaifen esin and hydrocodone formulations are achieved by adjust EXAMPLE 5 ing the composition and thickness of the granule coatings Sustained Release Formulation and the composition of the tableting excipients to vary the 0102 This example describes a sustained release formu release profile of sustained release guaifenesin followed by lation of a decongestant (guaifenesin) and a cough Suppres a sustained release of hydrocodone after the initial delay of sant (hydrocodone bitartrate). The formulation consists of approximately 4 hours. 1000 mg of guaifenesin, and 10 mg of hydrocodone bitar Formulation 1: trate. The formulation is manufactured as a matrix tablet 0112 Formulation 1 can be manufactured by first wet made by direct compression, and contains no immediate mixing (granulation) guaifenesin and hydroxypropyl meth release formulation of either guaifenesin or the hydrocodone ylcellulose, in a high-energy, high-shear mixer to produce bitartrate. The tablet is formulated so as to release guaifen dense guaifenesin pellets. In a similar process hydrocodone esin and hydrocodone over a period of 8 to 12 hours after and hydroxypropyl methylcellulose is mixed to produce ingestion. The formulation includes the following standard dense hydrocodone pellets. The resulting guaifenesin and excipients as shown in Table 4. hydrocodone pellets are sieved to the same size. The pellets are then combined and mixed with more hydroxypropyl TABLE 4 methylcellulose and compressed into tablets. The resulting tablets are then formed by a mixture of hydroxypropyl Dicalcium phosphate dihydrate methylcellulose-guaifenesin granulation, hydroxypropyl Croscarmellose sodium Methocel(R) K10OM methylcellulose-hydrocodone granulation and additional Silicon Dioxide hydroxypropyl methylcellulose. Microcrystalline cellulose PH 102 (sustained release component) 0113. Once the formulations are swallowed or consumed, Magnesium Stearate the tablets become wet and the hydroxypropyl methylcel lulose surrounding the tablets is believed to form thin gel layers. Any granular guaifenesin exposed to the exteriors of EXAMPLE 6 the tablets will dissolve out of the tablets, resulting in an intermediate rate of guaifenesin for absorption. As the Immediate and Sustained Release Formulation guaifenesin leaves the outer Surfaces of the tablets, gas 0103) This example describes a sustained release formu trointestinal fluid can reach deeper into the tablets, resulting lation of a decongestant (guaifenesin) and a cough Suppres in thicker gel layers and the dissolution of the intermediate sant (hydrocodone bitartrate) with an immediate release release guaifenesin granules Surrounded by the gel layers. cough Suppressant (hydrocodone bitartrate) component. The The gel layers then act as controlled release layers for sustained release formulation core consists of 1000 mg of dissolved guaifenesin originating in the intermediate release guaifenesin, and 5 mg of hydrocodone bitartrate. The for guaifenesin granules. Erosion of the gel layers results in mulation is manufactured as a matrix tablet made by direct further drug release. Hydrocodone is released in a similar compression, and contains no immediate release formulation fashion from hydrocodone granules. US 2007/01.41 147 A1 Jun. 21, 2007

0114. Additional polymers such as hydroxypropyl meth USP, the unit is granulated for about 5 minutes. Hydroc ylcellulose of differing molecular weights or ethylcellulose odone granules are processed in a similar fashion. The in the hydrocodone granules are added to delay the release granulated unit is discharged into double polyethylene-lined of hydrocodone for approximately 4 hours. An exemplary containers and then manually loaded into a Glatt R bowl Swelling agent is hydroxypropyl methylcellulose, in an while being passed through a #4 mesh screen. The Glatt R. amount ranging from about 5% to about 50% parts by bowl is loaded into a Glatt TFO-60 fluid-bed drier with an weight per 100 parts by weight of tablet or formulation. inlet air temperature setting of about 70° C.-0.5°C. The unit 0115 The formulation ensures sustained time release is dried until a moisture level of 0.1+1.0% is obtained as over a period of approximately 8 to 12 hours as demon determined using a ComputracR. Moisture Analyzer, model strated by in vitro dissolution techniques known to those MASA. The dried granulation is discharged into appropri skilled in the art. A binder may also be employed, preferably ately labeled, double polyethylene-lined drums and recon a material Such as one or more of a group of polymers having ciled. The dried and reconciled granulation is then passed the repeating unit of 1-ethenyl-2-pyrrolidinone. These poly through a Kemutec R. BetaGrind mill equipped with a 1.5 mers generally have molecular weights of between about mm screen and running at approximately 1500 RPM. The 10,000 and 700,000 Daltons, and are also known as “povi milled granulation is collected into appropriately labeled, done'. Amounts of the binder material will vary depending double polyethylene-lined drums and reconciled. The milled upon the nature of the binder and the amount of other granulation is sampled and tested by Quality Control and ingredients of the compositions. An exemplary amount of released prior to further processing. The released guaifen povidone is from about 1% to about 5% by weight of esin and hydrocodone granulation units are charged to a povidone per 100 parts by weight of the total formulation. Patterson-Kelley 20 ft3 V-blender after which they are Processing aids such as lubricants, including Stearic acid, blended together for about 10+ 1 minutes and then dis may also be employed, as is known in the art. An exemplary charged to appropriately labeled, double polyethylene-lined amount of stearic acid is from about 0.5% to about 2.0% by containers. weight per 100 parts by weight of table or formulation. One 0.122 Guaifenesin and hydrocodone tablets are formu composition of formulation 1 is provided in Table 4: lated from a common granulation which is blended with appropriate quantities of Methocel(R), USP E10M Premium TABLE 4 CR Grade and Stearic Acid, NF to achieve the final dosage formulation. Tablet Composition Ingredient Weight (mg) Formulation 2: Guaifenesin 1OOO I0123 Dense pellets of guaifenesin and hydrocodone are Hydrocodone 10 prepared according to the wet granulation procedure for Hydroxypropyl methylcellulose 406 Povidone 35 Formulation 1 as described in Example 7. Sized granules of Stearic Acid 15 guaifenesin are coated with an aqueous ethylcellulose dis persion (SURERELEASETM) in a fluid bed with Wurster TOTAL 1466 configuration, using a temperature of 42-44° C. and a spray rate of 0.5 g/min. Delayed release granules of hydrocodone 0116 Granulation Process Description are coated with a latex dispersion of acrylic acid polymers 0117 The unprocessed guaifenesin and hydrocodone raw (Eudragit(R) RS) in a fluid bed with Wurster configuration. materials are dispensed and granulated in a high shear Guaifenesin and hydrocodone tablets are manufactured as in granulator. The wet granules are sieved into a fluid bed drier Formulation 1. ad dried. When the drying process is complete, the granules 0.124 Modifications and variations of the present inven are milled. Milling ensures uniform particle size distribution tion will be apparent to those skilled in the art in view of the throughout the guaifenesin and hydrocodone granules. foregoing description and are intended to be encompassed 0118 Tablet Process Description by the following claims. All references cited herein are 0119 The guaifenesin and hydrocodone tablet blend is specifically incorporated by reference. manufactured by blending the guaifenesin and hydrocodone We claim: granulations, extragranular Methocel(R) E10M and Hys 1. A mixed release composition for oral administration trene(R) 5016 (Stearic acid). A guaifenesin and hydrocodone comprising two or more drugs acting on different symptoms tablet blend is compressed to form guaifenesin and hydro formulated for a combination of immediate release, codone tablets. extended release, and delayed release, wherein the first drug 0120 Manufacturing Process is sequentially released prior to release of the second or more 0121 The guaifenesin and hydrocodone tablets may be drugs, to provide an effect that enhances action of the second manufactured by the following possible manufacturing pro drug. cess. A Littleford(R) FM 130 granulator is charged with 2. The composition of claim 1, wherein the two or more approximately one half of the guaifenesin, USP required for drugs are selected from the group consisting of deconges the process unit (about 17.4 kg) followed by about 4.00 kg tants, antihistamines, expectorants, antitussives, cough Sup of Methocel(R), USP E10M Premium CR Grade; and 1.20 kg pressants, drying agents, and combinations thereof. of Povidine, USP; and the balance of the guaifenesin (about 3. The composition of claim 2, wherein the decongestant 17.40 kg). The powder bed is dry mixed in the Littleford(R) is selected from the group consisting of phenylephrine, FM130 granulator, with choppers on, for approximately 1 phenylpropanolamine, pseudoephedrine, pharmaceutically minute. At the completion of the 1-minute pre-mix cycle, acceptable salts thereof, and combinations thereof. about 12.0+0.05 kg of Purified Water, USP are sprayed onto 4. The composition of claim 2, wherein the antihistamine the powder bed at a rate of about 2.40+0.24 kg/minute. is selected from the group consisting of chlorpheniramine, Immediately following the addition of the Purified Water, brompheniramine, dexchloropheniramine, dexbromophe US 2007/01.41 147 A1 Jun. 21, 2007 niramine, triprolidine, diphenhydramine, doxylamine, tripe 12. The composition of claim 9 wherein the pharmaceu lennamine, cyproheptatine, bromodiphenhydramine, phen tical composition includes: indamine, pyrilamine, azatadine, pharmaceutically (a) an immediate release expectorant active drug pack acceptable salts thereof and combinations thereof. aged for immediate release of over 60-80% of the 5. The composition of claim 2, wherein the expectorant is active drug within from about 90 minutes to about 120 selected from the group consisting of guaifenesin, terpin minutes following dosing: hydrate, (glyceryl guaiacolate), potassium guaiacolsul (b) an extended release expectorant active drug packaged fonate, pharmaceutically acceptable salts thereof, and com for extended release of over 90% of the active drug binations thereof. released substantially linearly over up to at least a 12 6. The composition of claim 2, wherein the antitussive is hour period of time; selected from the group consisting of caramiphen, dex (c) an antitussive active drug packaged for delayed and tromethorphan, codeine, hydrocodone, pharmaceutically extended release of over 90% of the antitussive active acceptable salts thereof, and combinations thereof. drug released substantially linearly over up to at least 7. The composition of claim 2, wherein drying agent is an 8 hour period following an initial delay of release of selected from the group consisting of methScopolamine, from about 2 to about 4 hours; and Scopolamine, meclizine, trimethobenzamide, dimenhydri (d) optionally a drying agent active drug packaged for nate, cyclizine, pheniramine, buclizine, chlorpheniramine, delayed and extended release of over 90% of the active diphenhydramine, homatropine, carbinoxamine, clemastine, drug released substantially linearly over up to at least brompheniramine, and doxylamine. an 8 hour period following an initial delay of release of 8. The composition of claim 2, wherein the cough Sup from about 2 to about 4 hours. pressant is selected from the group consisting of benzona 13. The composition of claim 9 wherein the pharmaceu tate, bromodiphenhydramine, brompheniramine, buclizine, tical composition includes: carbinoxamine, chlorpheniramine, clemastine, codeine, cyclizine, dexchloropheniramine, dextromethorphan, dihy (a) an immediate release expectorant active drug pack drocodeine, dimenhydrinate, diphenhydramine, doxy aged for immediate release of over 60-80% of the lamine, homatropine, hydrocodone, meclizine, pheniramine, active drug within from about 90 minutes to about 120 phenyltoloxamine, pyrilamine, trimethobenzamide, triproli minutes following dosing: dine. (b) an extended release expectorant active drug packaged 9. The composition of claim 2 comprising an expectorant for extended release of over 90% of the active drug of immediate and extended release, wherein over 90% of the released substantially linearly over up to at least a 12 drug is released substantially linearly over a 12 hour period hour period of time; of time, and a cough Suppressant for delayed and extended (c) an antitussive active drug packaged for delayed and release, wherein over 90% of the drug is released between extended release of over 90% of the active drug 4 and 12 hours, wherein the release profiles of the ingredi released substantially linearly over up to at least an 8 ents are orchestrated to coordinate the production and clear hour period following an initial delay of release of from ance of mucus and cough suppression. about 2 to about 4 hours; and 10. The composition of claim 2 comprising: (d) optionally a drying agent active drug packaged for (a) an anti-tussive active drug within a granule matrix delayed and extended release of over 90% of the active packaged for extended release of over 90% of the drug released substantially linearly over up to at least active drug released substantially linearly over a 12 an 8 hour period following an initial delay of release of hour period of time; from about 2 to about 4 hours. (b) an anti-histamine active drug packaged for extended 14. The composition of claim 9 wherein the pharmaceu release of over 90% of the active drug released sub tical composition includes: stantially linearly over a 12 hour period of time; and (a) an extended release expectorant active drug packaged (c) a drying agent active drug packaged for delayed and for extended release of over 90% of the expectorant extended release of over 90% of the active drug active drug released substantially linearly over up to at released substantially linearly over a period of 8 hours least a 12 hour period of time; and following an initial delay of release of from about two (b) an antitussive active drug formulated for delayed and to about four hours. extended release, wherein over 90% of the antitussive 11. A composition of claim 2 wherein the pharmaceutical active drug is released substantially linearly over up to composition comprises: at least an 8 hour period following an initial delay of (a) an immediate release decongestant active drug pack release of from about 2 to about 4 hours. aged for immediate release of over 60-80% of the 15. The composition of claim 9 wherein the pharmaceu active drug within from about 90 minutes to about 120 tical composition includes: minutes following dosing: (a) an extended release expectorant active drug packaged (b) an extended release decongestant active drug pack for extended release of over 90% of the expectorant aged for extended release of over 90% of the active active drug released substantially linearly over up to at drug released substantially linearly over a 12 hour least a 12 hour period of time; and period of time; and (b) an antitussive active drug packaged for Sustained (c) a drying agent active drug packaged for delayed and release such that up to 20% of the antitussive active extended release of over 90% of the active drug drug can be released in a Sustained fashion over the first released substantially linearly over an 8 hour period 1 to 4 hours, followed by the sustained release of up to following an initial delay of release of from about two 100% of the antitussive active drug between 4 to 12 to about 4 hours. hours. US 2007/01.41 147 A1 Jun. 21, 2007

16. The composition of claim 9 wherein the pharmaceu release matrix, a Sustained release bead, a Sustained release tical composition includes: matrix, and combinations thereof. (a) an extended release expectorant active drug packaged 22. The composition of claim 9 wherein the expectorant for extended release of over 90% of the expectorant is guaifenesin in the form selected from the group consisting active drug released substantially linearly over up to at of an immediate release bead, an immediate release matrix, least a 12 hour period of time; and a Sustained release bead, a Sustained release matrix, and (b) an antitussive active drug packaged for Sustained combinations thereof. release wherein the antitussive active drug is released 23. The composition of claim 9 wherein the antitussive is in a first immediate release pulse, such that up to 50% hydrocodone in a form selected from the group consisting of of the antitussive active drug is released in a Sustained an immediate release bead, an immediate release matrix, a fashion over the first 1 to 4 hours, followed by a Sustained release bead, a Sustained release matrix, and sequential immediate release pulse of the antitussive combinations thereof. active drug, such that up to 100% of the antitussive 24. The composition of claim 9 wherein the tablet is in the active drug is released between 4 to 6 hours. form of a rapid dissolving tablet. 17. The composition of claim 9 wherein the pharmaceu 25. The composition of claim 9, comprising different tical composition includes: types of coated beads or granules into a capsule, wherein (a) an extended release expectorant active drug packaged each type of coated bead or granule includes individually an for extended release of over 90% of the expectorant extended release anti-tussive, an extended release antihista active drug released substantially linearly over up to at mine and drying agent in a delayed release form, and least a 12 hour period of time; and wherein the capsule further includes one or more excipients. (b) an antitussive active drug packaged for immediate and 26. The composition of claim 9, comprising a mixture of sustained release, such that up to 50% of the antitussive excipients and a mixture of granules into a tablet, wherein active drug is released in immediate fashion over the each type of granule includes individually an extended first 1 to 4 hours, followed by sustained release of the release anti-tussive, an extended release antihistamine and a antitussive drug, such that up to 100% of the antitussive drying agent in a delayed release form. active drug is released between 4 to 12 hours. 18. The composition of claim 9 wherein the pharmaceu 27. The composition of claim 9 wherein the mixture of tical composition includes: excipients further includes free active drug. (a) an extended release expectorant active drug packaged 28. The composition of claim 9 comprising a formulation for extended release, of hydrocodone and guaifenesin, wherein release of hydro wherein 20 to 35% of the expectorant active drug is codone is achieved in a series of sequential immediate released between 0 to 20 hours, 35-65% of the expec release pulses for up to 12 hours after administration. torant active drug is released between 2 to 4 hours, and 29. The composition of claim 9 comprising hydrocodone 65-90% of the expectorant active drug is released and guaifenesin in claim 9, wherein 25-50% of the hydro between 4 to 8 hours; and codone is released as an immediate release pulse within 1-4 an antitussive active drug. h after administration, and 50-100% of the hydrocodone is 19. The composition of claim 9, wherein the pharmaceu released as a second immediate release pulse within 4 to 12 tical formulation is in a form selected from the group hours after administration. consisting of a capsule, tablet, oral rapid dissolving tablet, 30. The composition of claim 9 comprising hydrocodone softgel, gelcap, film, gum, pastille, lozenge, disk, and wafer. and guaifenesin in claim 9, wherein up to 100% of the 20. The composition of claim 9 wherein the anti-tussive hydrocodone is released as a single immediate release active drug is dextromethorphan in the form selected from component 2 to 15 hours after administration. the group consisting of an immediate release bead, an 31. The composition of claim 9, comprising hydrocodone immediate release matrix, a Sustained release bead, a sus and guaifenesin, wherein 25-50% of the hydrocodone is tained release matrix, and combinations thereof the anti released in a Sustained fashion during the first 1 to 4 hours histamine active drug is chlorpheniramine in a form selected after administration, which is followed by sustained release from the group consisting of an immediate release head, an of 25 to 100% of the hydrocodone between 4 to 12 hours immediate release matrix, a Sustained release bead, a sus after administration. tained release matrix, and combinations thereof, and the 32. The composition of claim 9 comprising hydrocodone drying agent active drug is methScopolamine in a form and guaifenesin, wherein (i) 20 to 35% of guaifenesin is selected from the group consisting of an immediate release released within 2 hours of administration, (ii) 35-65% is bead, an immediate release matrix, a Sustained release bead, released between 2 to 4 hours after administration and (iii) a Sustained release matrix, and combinations thereof. 65-90% is released between 4 to 8 hours after administra 21. The composition of claim 9 wherein the decongestant tion. is pseudoephedrine in the form selected from the group consisting of an immediate release bead, an immediate