USOO884O924B2

(12) United States Patent (10) Patent No.: US 8,840,924 B2 Tengler et al. (45) Date of Patent: Sep. 23, 2014

(54) COMPOSITIONS AND METHODS OF 5,980,945. A 1 1/1999 Ruiz MAKING RAPIDLY DISSOLVING 6,120,787 A 9/2000 Gustafsson et al. ONICALLY MASKED FORMULATIONS 6,613.3586,596,311 B1*B2 9/20037/2003 RandolphDobetti ...... et al. 424/464 (75) Inventors: Mark Tengler, Colleyville, TX (US); 7:6 R: ck 1929: Na et al...... 424/489 Russell McMahen, Flower Mound, TX 800s,378 B2 8, 2011 Hargens et al. (US) 2003/017031.0 A1* 9, 2003 Wadhwa ...... 424/486 2004/0228830 A1 11/2004 Hirsh et al. (73) Assignee: NEOS Therapeutics, LP, Grand Prairie, 2005.0036977 A1 2/2005 Gole et al. TX (US) 2005/0181050 A1* 8, 2005 Hirsh et al...... 424/469 2005/0281875 A1 12/2005 Srinvasan et al.

(*) Notice: Subject to any disclaimer, the term of this 3.9. 5. A. g3. E. et al ...... :3. engler et al...... past its.listed under 35 2007/0202167 A1* 8, 2007 Srinivasan et al...... 424/468 .S.C. 154(b) by ayS. 2010/0092564 A1 4, 2010 Park et al.

(21)21) Appl. No.:No 12/717,2519 OTHER PUBLICATIONS (22) Filed: Mar. 4, 2010 CODEPREX (Chlorpheniramine Polistirex: Codeine Polistirex) (65) Prior Publication Data Drug Information, “Drugs-About.com” (2004). Jeong, U.S. Appl. No. 60/624.959, filed Nov. 4, 2004. US 2010/0278.901 A1 Nov. 4, 2010 Park, U.S. Appl. No. 60/468.449, filed May 7, 2003. O O Center for Drug Evaluation and Research (CDER), “Guidance for Related U.S. Application Data Industry: Orally Disintegrating Tablets.” US Department of Health (63) Continuation of application No. 1 1/255,555, filed on and Human Services, Food and Drag Administration (Dec. 2008), pp. Oct. 21, 2005, now abandoned. 1-3. (51) Int. Cl. * cited by examiner A69/20 (2006.01) A6 IK9/46IK 9/26 30:2006.O1 8: Primary Examiner — Susan Tran A6 IK 47/48 (2006.01) (74) Attorney, Agent, or Firm — Hunton & Williams LLP A6 IK9/00 (2006.01) A 6LX3L/785 (2006.01) (52) U.S. Cl. (57) ABSTRACT CPC ...... A61K 9/0056 (2013.01); A61K47/48.184 (2013.01); A61 K3I/785 (2013.01) The present invention includes compositions and methods for USPC 424/466. 424/464. 424/468: 424/469 reduce the taste of the drug in the drug resin complex. The (58) Field o ?classification search s s composition may include one or more drug-resin complexes None and a highly compressible, free-flowing pharmaceutical See application file for complete search history. excipient. The resin is present in an amount effective to reduce the taste of the drug in the drug resin complex relative (56) References Cited to an otherwise identical pharmaceutical composition with out the resin; and wherein the highly compressible, free U.S. PATENT DOCUMENTS flowing pharmaceutical excipient causes release of the drug 2.990,332 A 6/1961 Keating resin complex in the mouth. 3,594,470 A * 7/1971 Borodkin et al...... 424/483 4.959,219 A * 9/1990 Chow et al...... 424/480 5,674,533 A 10, 1997 Santus et al. 25 Claims, No Drawings US 8,840,924 B2 1. 2 COMPOSITIONS AND METHODS OF The microgranules have a moguisteine core, with one or more MAKING RAPIDLY DISSOLVING optional plasticizers and excipients, granulated into micro ONICALLY MASKED FORMULATIONS granules having sizes Smaller than 500 uniform Surfaces, Substantially spherical shapes, apparent densities of about CROSS-REFERENCE TO RELATED 500 to 600 g/l and very low friabilities, which are made by APPLICATION wet-kneading micronised moguisteine using water or a mix ture of water and other solvents. These initial microgranules This application is a Continuation of U.S. application Ser. have controlled-release properties by, a first coating having No. 1 1/255,555 filed Oct. 21, 2005 now abandoned, the dis essentially hydrophilic characteristics, which isolates the closure of which is herein incorporated by reference in its 10 microgranules; followed by a second coating having lipo entirety. philic characteristics on top of the first coating; and a third coating having hydrophilic characteristics. FIELD OF INVENTION Orally administered drug formulations may be provided to the patient in many dosage forms, including Solid forms (e.g., The invention relates to compositions and methods of mak 15 capsules, caplets, effervescent or tablets) and liquid forms ing rapidly disintegrating or chewable, Sustained-release for (e.g., Solutions, syrups, emulsions or Suspensions). Gener mulations, and more particularly, to compositions and meth ally, orally administered drug formulations administered in ods for making rapidly disintegrating ionically masked solid dosage form are intended to be swallowed whole and formulations. any disagreeable taste can be easily masked with an exterior coating. However, some formulations are designed for rapid BACKGROUND OF THE INVENTION absorption of the active ingredient through the oral mucosa, e.g., chewing of the tablets, effervescent, and the like and thus Without limiting the scope of the invention, its background result in tastes that are more difficult to mask. A growing is described in connection with ionically masked pharmaceu market for these and other products is the pediatric and geri tical agents that are rapidly disintegrating and delivered in an 25 atric patients. extended or Sustained-release form, as an example. Many pharmaceutical compositions must be formulated as Methods for sustained release are known in the art. One liquids for use by pediatric, geriatric patients, disabled per Such method of making Sustained release particles is taught in Sons, incapacitated patients and persons with dysphagia often U.S. Pat. No. 6,120,787, issued to Gustafsson, et al., which have trouble swallowing. To alleviate this challenge a number teach a method for preparing parenterally administrable Sus 30 of drug delivery protocols have been developed including tained release microparticles. The method includes preparing rapid in-mouth disintegrating tablets, tablets which disinte core particles in an aqueous medium that is essentially free grate in liquid prior to ingestion, liquids and syrups, gums and from organic solvent and the biologically active Substance is transdermal compositions. Unfortunately, these delivery entrapped therein during or after preparation, e.g., drying the methods can pose their own problems. core particles. The coating may be the same release-control 35 For example, immediate release compositions with rapid ling polymer, which is added by an air Suspension technique absorption of the active ingredient through the oral mucosa to create a shell on the core particles without any detrimental (e.g., rapid in-mouth disintegrating tablets, tablets that disin exposure of the active Substance to organic solvent. tegrate in liquid prior to ingestion, liquids and syrups, gums) Another Sustained-release composition includes an amor may have an unpleasant texture or even an unpalatable taste phous polymeras taught in U.S. Pat. No. 6,613.358, issued to 40 associated with the immediate release agent or other compo Randolph, et al., which provides for a Sustained release com nent of the composition. position of a pharmaceutical Substance that includes: a bio compatible polymer that is highly amorphousand a pharma SUMMARY OF THE INVENTION ceutical Substance in a hydrophobic ion complex with an amphiphilic material. A compressed antisolverit method for 45 The present inventors recognized that certain drugs pro manufacturing the composition it also taught, as are various duce an unpalatable taste associated with the immediate product forms incorporating the composition and various release agent that are not effectively masked by traditional uses for the composition. taste masking techniques. The present invention addresses the Yet another Sustained release drug formulation is taught in problems associated with the delivery of one or more active U.S. Pat. No. 5,980,945, issued to Ruiz in which a sustained 50 agents in a Solid dosage form under controlled conditions. release drug formulation includes a drug; a biodegradable Solid, chewable formulations are often preferred by many polymer that is insoluble in water; and an oil vehicle in which users due to the easy of delivery, namely, natural chewing and both the drug and the polymer are dissolved. The oil vehicle Swallowing thereby leading to increased compliance with may contain 10-100% by volume of a pharmaceutically dosing regimens. Many children and adults fail to comply acceptable oil and 0-90% by volume of a pharmaceutically 55 with dosing instructions due to the size, shape, taste and/or acceptable liquid carrier for the drug or the polymer. mouth-feel of, e.g., tablets, caplets and even gelcaps. Finally, U.S. Pat. No. 5,674,533 issued to Santus, et al., The present inventors further recognized that delivery of teaches pharmaceutical compositions for the controlled agents in a chewable formulation is not always preferred by release of the anti-tussive, moguisteine, in a liquid Suspension users because of the taste and/or mouth feel of the active designed either as ready-to-use and time-stable liquid formu 60 agents and/or excipients often included with chewable for lations with a shelf-life of at least two years, or as dry formu mulations. What is needed are formulations that are manu lations that are reconstituted with water when needed and factured using commonly used equipment, are shelf-stable then remain stable throughout the treatment period. Santus have improved mouth-feel (e.g., less grainy, bitter or slimy) teaches the use of coated microgranules for the controlled and provide actual controlled, Sustained, mixed or modified release of moguisteine having sizes ranging from 50 to 500 65 release. Finally, it was recognized that despite many decades um, preferably from 90 to 300 um, which are capable of of research and development, controlled-release formula remaining easily in Suspension in a liquid for extended times. tions have not been amenable to large-scale production in US 8,840,924 B2 3 4 facilities and to amounts that are permissible for industrial ars. The hyoscyamine is released slowly when the composi applicability of controlled-release chewable formulations. tion is chewed, the composition becoming thixotropic when However, despite the many known techniques for eliminating chewed but not fully dissolving for at least 30 seconds when the problems commonly associated with the manufacture of chewed, and the composition slowly dissociates when chewable formulations, and hence their widespread failure, 5 chewed, to Substantially dissociate thereafter in saliva during none of these formulations have solves the problems of chewing. patient compliance due to taste and mouthfeel. The present invention includes a chewable tablet in which More particularly, the present invention includes compo a pharmaceutically active drug-resin complex is slowly sitions and methods for preparing a chewable, controlled released when the tablet is chewed. As the tablet is chewed it release formulation by blending one or more controlled 10 becomes thixotropic but not fully dissociated for at least 10 release microbeads having one or more active agents with one seconds. The tablet may slowly dissociate thereafter in saliva or more microbeads. The one or more microbeads may during chewing or once Swallowed for up to 24 hours. The include an enteric coat, a resin coat, a lacquer coat, a pH chewable formulation may include a portion of the one or sensitive coating, a biodegradable polymer matrix, a water more beads with an immediate release profile and another soluble matrix, an ionic matrix, combinations and mixtures 15 portion with a controlled or delayed release profile. In one thereof The one or more microbeads may also include one or example, the active agent may be included in two different more polymers selected from cellulose, ethylcellulose, meth salt forms or on two different resins, wherein the active agent ylcellulose, propylcellulose, methoxypropylcellulose, cellu is differentially released or becomes dissolved and/or bio lose nitrate, poly(vinyl alcohol), poly(vinyl chloride), poly available at a different rate from the second salt or released styrene, polyethylene, polypropylene, poly(ethylene-co from the second bead. When using an ion-exchange matrix, vinyl acetate), poly(hydroxybutyric acid), poly bead or resin to retain the one or more active agents the liquid (hydroxyvalerianic acid-co-hydroxybutyric acid), poly(lactic Solution will in some cases be a low-ionic strength, depending acid), poly(glycolic acid), poly(lactic acid-co-glycolic acid), on the nature of the ion-exchange matrix and the one or more poly(e(-caprolactones), poly(e-caprolactone-co-DL-lactic active agents. Based on the present disclosure, the skilled acid), poly(maleic anhydride), polyamides, gelatin, chitosan, 25 artisan may easily determine the best matrix for a particular collagen, poly(hydroxyalkyl)-L-glutamines, poly(Y-ethyl-L- active, determine the amount of loading (theoretical and glutaminate-co-glutamic acid), poly(L-leucine-co-L-aspartic empirical), and the conditions for retention and release. acid), poly(proline-co-glutamic acid), poly(alkyl 2-cy Examples of active agents that may be provided as part of anoacrylates), polyurethanes, poly(methyl methacrylate), the chewable formulations of the present invention include poly(methyl methacrylate-co-methacrylic acid) and poly 30 Vitamins, minerals, nutritional Supplements, herbal extracts, (methacrylate-co-hydroxypropyl methacrylate), polystyrene, gums, gels, oils, salts, mixtures and combinations thereof. polistirex, polacrilex and salts, combinations and mixtures Pharmaceutical active agents may include, e.g., protein, pep thereof. tide, carbohydrate, polysaccharide, glycoprotein, lipid, hor The present invention may be, e.g., a taste-masked soluble mone, growth factor, cytokine, interferon, receptor, antigen, chewable pseudoephedrine and chlorpheniramine pharma 35 allergen, antibody, antiviral, antifungal, antihelminthic, Sub ceutical composition. The composition includes a pseu strate, metabolite, cofactor, inhibitor, drug, nutrient, toxin, doephedrine-resin complex, a chlorpheniramine-resin com poison, explosive, pesticide, chemical warfare agent, biowar plex and one or more amorphous Sugars. The composition fare agent, biohazardous agent, infectious agent, prion, radio may be a compressible, free-flowing, pharmaceutical, taste isotope, vitamin, heterocyclic aromatic compound, carcino masking excipient, wherein the highly compressible, free 40 gen, mutagen, narcotic, amphetamine, barbiturate, flowing pharmaceutical excipient aids the release of the drug hallucinogen. In some cases the chewable may be, eg., a resin complex in the mouth. vaccine for against a virus, bacterium, helminth and/or fungi, The present invention provides a method of masking the fragments, receptors or toxins thereof, e.g., Salmonella, taste of a rapidly disitegrating or chewable, taste-masked Streptococcus, Brucella, Legionella, E. coli, Giardia, pharmaceutical composition by adding one or more amor 45 Cryptosporidium, Rickettsia, spore, mold, yeast, algae, phous Sugars to a pharmaceutically active drug-resin com amoebae, dinoflagellate, unicellular organism, pathogen, plex. A taste-masked soluble chewable composition may cell, combinations and mixtures thereof The one or more include pseudoephedrine and chlorpheniramine in a thera active agents may be a pharmaceutical agent, an enzyme, a peutically effective amount formed into a pharmaceutical cytokine, a growth promoting agent, an antibody, an antigen, composition. The composition may include a pseudoephe 50 a hormone, a vaccine, a cell, a live-attenuated pathogen, a drine-resin complex, a chlorpheniramine-resin complex, one heat-killed pathogen, a virus, a bacteria, a fungi, a peptide, a or more amorphous Sugars and a compressible, free-flowing, carbohydrate, a nucleic acid, a lipid, mixtures and combina pharmaceutical, taste-masking excipient. The pseudoephe tions thereof. drine and the chlorpheniramine are slowly released as the Specific examples of active agents include: Steroids, respi composition is chewed. The composition becoming thixotro 55 ratory agents, sympathomimetics, local anesthetics, antimi pic when chewed but not fully dissolving for at least 10 crobial agents, antiviral agents, antifungal agents, antihelm seconds, so as to dissolve thereafter in Saliva during chewing. inthic agents, insecticides, antihypertensive agents, The present invention includes a rapidly dissolving, taste antihypertensive diuretics, cardiotonics, coronary vasodila masked hyoscyamine pharmaceutical composition. The com tors, vasoconstrictors, B-blockers, antiarrhythmic agents, cal position includes a hyoscyamine-resin complex, one or more 60 cium antagonists, anti-convulsants, agents for dizziness, tran amorphous Sugars and a compressible, free-flowing, pharma quilizers, antipsychotics, muscle relaxants, drugs for ceutical, taste-masking excipient. The hyoscyamine is Parkinson's disease, respiratory agents, hormones, non-ste released slowly when the tablet disintegrates or is chewed. roidal hormones, antihormones, vitamins, antitumor agents, The rapidly disintegrating, taste-masked pharmaceutical miotics, herb medicines, herb extracts, antimuscarinics, inter composition may include any salt of hyoscyamine, e.g., an 65 ferons, immunokines, cytokines, muscarinic cholinergic ionically bound hyoscyamine. The composition may be a blocking agents, mydriatics, psychic energizers, humoral hyoscyamine-resin complex and one or more amorphous Sug agents, antispasmodics, antidepressant drugs, anti-diabetics, US 8,840,924 B2 5 6 anorectic drugs, anti-allergenics, decongestants, expecto perceptions. Conventional Sweeteners and/or flavors are com rants, antipyretics, antimigrane, anti-malarials, anti-ulcer monly used to prevent the taste from being apparent during ative, anti-estrogen, anti-hormone agents, anesthetic agent, or the time that the medicine is in the mouth. drugs having an action on the central nervous system. For The present invention may be used to taste-mask a wide example, for use in the treatment of cold/cough symptoms the range of chemicals in a formulation depending on the pre active agents may include one or more antihistamines, anti dominant, secondary and tertiary taste. The selection of two, tussives, expectorants and the like, e.g., hyoscyamine, pseu three or more masking agents may be modified, without doephedrine, chlorpheniramine, dextromethorphan, guaifen undue experimentation, by comparing the most common pre esin, and salts thereof or mixtures of salts thereof. The dominant, secondary and tertiary flavors or taste of the one or chewable formulation may also include an analgesic or even 10 more actives. Differences may also be determined between a narcotic. children and adults (e.g., changes in Sweetness thresholds), Examples of carriers for the actives of the present invention males and females and in accordance with the flavor of the include any degradable, partially degradable or non-degrad final composition (e.g., cherry versus grape). able and generally biocompatible polymer, e.g., polyStirex, The sense of taste caused by the excitation of taste recep polypropylene, polyethylene, polacrilex, poly-lactic acid 15 tors on the tongue. The tongue includes receptors for a large (PLA), poly-glycolic acid (PGA) and/or poly-lactic poly number of specific chemicals have been identified that con glycolic acid (PGLA) in the form or a matrix or even a bead. tribute to the reception of taste, e.g., chemicals as Sodium, The present invention also includes those chewable formu potassium, chloride, glutamate and adenosine. Despite this lations made by the methods disclosed and claimed herein. complexity, five types of tastes are commonly recognized: For example, specific chewable formulation may include one Salty, Sour, Sweet, Bitter and Umami. The umami taste is that or more active agents available for immediate, modified and/ of monosodium glutamate and has recently been recognized or extended or controlled release for use in treating cold/ as a unique taste, as it cannot be elicited by any combination coughfallergy symptoms. The one or more actives for cold/ of the other four taste types. Glutamate is present in a variety coughfallergy may include one or more of the following: of protein-rich foods, and particularly abundant in aged anti-tussives, anti-histamines, expectorants and analgesics. 25 cheese. For example, the actives may include hyoscyamine, pseu The perception of taste may also be influenced by thermal doephedrine, chlorpheniramine, dextromethorphan, guaifen stimulation of the tongue. For example, in Some people, esin, and salts thereof or mixtures of salts thereof. warming the front of the tongue produces a clear Sweet sen sation, while cooling leads to a salty or sour sensation. Tastes DETAILED DESCRIPTION OF THE INVENTION 30 are based on human sensations and some physiologists believe that each animal probably has its own perception of While the making and using of various embodiments of the taste. present invention are discussed in detail below, it should be As used herein, the terms "extended release.” “sustained appreciated that the present invention provides many appli release,” and “delayed release' are used to define a release cable inventive concepts that can be embodied in a wide 35 profile to effect delivery of an active over an extended period variety of specific contexts. The specific embodiments dis of time, defined herein as being between about 60 minutes cussed herein are merely illustrative of specific ways to make and about 2, 4, 6, 8 or even 12 hours. Extended release may and use the invention and do not delimit the scope of the also be defined functionally as the release of over 80 to 90 invention. percent (%) of the active ingredient after about 60 minutes To facilitate the understanding of this invention, a number 40 and about 2, 4, 6 or even 8 hours. Extended release as used of terms are defined below. Terms defined herein have mean herein may also be defined as making the active ingredient ings as commonly understood by a person of ordinary skill in available to the patient or Subject regardless of uptake, as the areas relevant to the present invention. Terms such as “a”, some actives may never be absorbed by the animal. Various “an and “the are not intended to refer to only a singular extended release dosage forms may be designed readily by entity, but include the general class of which a specific 45 one of skill in art as disclosed herein to achieve delivery to example may be used for illustration. The terminology herein both the Small and large intestines, to only the Small intestine, is used to describe specific embodiments of the invention, but or to only the large intestine, depending upon the choice of their usage does not delimit the invention, except as outlined coating materials and/or coating thickness. in the claims. As used herein, the term “USP is used to describe the Pharmaceutically active agents can be administered to the 50 United States Pharmacopoeia a widely recognized organiza patient in many forms with oral administration being the most tion that sets some of the standards that pharmaceutical popular as liquid Solutions, emulsions, Suspensions or in Solid manufacturers must meet to sell their drugs and drug com form Such as capsules or tablets. The oral administration is pounds in the United States. USP standards include proce problematic for some individual (e.g., infants, children and dures for the physical tests that must be performed on drugs older persons) that are unable to swallow whole tablets and 55 and drug compounds to ensure compliance with the specific capsules. Therefore, it is desirable to administer doses in a requirements set forth within these standards. liquid form, a dissolvable form, a chewable form or in a form As used herein, the term “pharmaceutically acceptable that are absorbed through the oral mucosa. salts' is used to describe those salts in which the anion (or Unlike tablets or capsules which are intended to be swal cation) does not contribute significantly to the toxicity or lowed whole, forms that are absorbed through the oral 60 pharmacological activity of the salt, and, as such, they are the mucosa must be formulated to take into account the taste of pharmacological equivalents of the bases of the compounds the active ingredient. Some therapeutic agents can cause to which they refer. Examples of pharmaceutically acceptable strong negative sensory perceptions in the mouth due to their acids that are useful for the purposes of salt formation include delivery through the mucosa. Often the sensory perceptions but are not limited to hydrochloric, hydrobromic, hydroiodic, are so objectionable that a patient stops taking the medicine. 65 citric, acetic, benzoic, mandelic, fumaric, succinic, phospho In Such cases, the use of conventional Sweetener/flavor ric, nitric, maleic, mucic, isethionic, palmitic, tannic and oth approach is not sufficient to mask or hide these negative ers. The active salt combinations of the pharmacologic ingre US 8,840,924 B2 7 8 dients may be the free acids, bases or as salts having anionic artisan will recognize that other combinations of actives, functional groups such asbitartrate, maleate, citrate, chloride, resins and Sugars may be used. bromide, acetate and sulfate. The source of the functional The present invention also includes a taste-masked soluble groups may be natural or synthetic. chewable pseudoephedrine and chlorpheniramine pharma As used herein, the term “Controlled release' refers to the ceutical composition. The composition includes a pseu release of an agent such as a drug from a composition or doephedrine-resin complex, a chlorpheniramine-resin com dosage form in which the agent is released according to a plex, one or more amorphous Sugars and a compressible, desired profile over an extended period of time. Controlled free-flowing, pharmaceutical, taste-masking excipient. The release profiles include, for example, Sustained release, pro pseudoephedrine and the chlorpheniramine are slowly longed release, pulsatile release, and delayed release profiles. 10 In contrast to immediate release compositions, controlled released when the composition is chewed. The composition release compositions allow delivery of an agent to a subject becoming thixotropic when chewed but not fully dissolving over an extended period of time according to a predetermined for at least 10 seconds, so as to dissolve thereafter in saliva profile. Such release rates can provide therapeutically effec during chewing. tive levels of agent for an extended period of time and thereby 15 The present invention includes a rapidly disintegrating, provide a longer period of pharmacologic or diagnostic taste-masked hyoscyamine pharmaceutical composition. The response as compared to conventional rapid release dosage composition includes a hyoscyamine-resin complex, one or forms. Such longer periods of response provide for many more amorphous Sugars and a compressible, free-flowing, inherent benefits that are not achieved with the corresponding pharmaceutical, taste-masking excipient. The hyoscyamine short acting, immediate release preparations. For example, in is slowly released as the tablet disintegrates. In some the treatment of chronic pain, controlled release formulations instances the resin is polistirex, polyacrilex or a combination are often highly preferred over conventional short-acting for thereof, and more specifically hyoscyamine polistirex. The mulations. amorphous Sugar may be the commercially available Pharm Controlled release pharmaceutical compositions and dos aburst or other Sugar known to the skilled artisan. age forms are designed to improve the delivery profile of 25 The present invention also includes a rapidly disintegrat agents. Such as drugs, medicaments, active agents, diagnostic ing, taste-masked hyoscyamine pharmaceutical composition. agents, or any Substance to be internally administered to an The composition includes a hyoscyamine-resin complex and animal, including humans. A controlled release composition one or more amorphous Sugars. The hyoscyamine is slowly is typically used to improve the effects of administered sub released when the composition is chewed, the composition stances by optimizing the kinetics of delivery, thereby 30 becoming thixotropic when chewed but not fully dissolving increasing bioavailability, convenience, and patient compli for at least 10 seconds when chewed, and the composition ance, as well as minimizing side effects associated with inap slowly dissolves when the composition is chewed, so as to propriate immediate release rates Such as a high initial release completely dissociate thereafter once swallowed. Alterna rate and, if undesired, uneven blood or tissue levels. tively, the active agent is slowly released when the composi The present invention provides a taste-masked pharmaceu 35 tion is chewed, the composition becoming thixotropic when tical composition including a drug-resin complex and a chewed but not fully dissolving for at least 10 seconds when highly compressible, free-flowing pharmaceutical excipient. chewed, and the composition slowly dissolves when the com The resin is present in an amount effective to reduce the taste position is chewed; however the remaining material need not of the drug in the drug resin complex by patients that is be swallowed and may be discarded. The present invention significant relative to an otherwise identical pharmaceutical 40 may be formulated in a variety of forms including a chewable composition without the resin. The highly compressible, free tablet, a solid, a liquid, a gel, a tab, a capsule, a disintegrating flowing pharmaceutical excipient the formulation to be com tablet, a powder, a lotion, a cream, a gum, a lozenge or pressed, while allowing for rapid disintegration or breakdown combination thereof. by chewing in the mouth. The pharmaceutical composition Generally, the drug-resin complex includes an exchange includes a chewable tablet, a Solid, a liquid, an orally disin 45 resin, e.g., cationic exchange resin. The resin may be divinyl tegrable tablet, a gel, a tab, a powder, a gum, a lozenge or a benzene Sulfonic acid cationic exchange resin, e.g., polis combination thereof. The disintegratable formulations may tirex. In some embodiments the drug-resin complex includes be delivered to, and adapted for, oral, nasal, buccal, ocular, pseudoephedrine polistirex, chlorpheniramine polistirex, urethral, transmucosal, vaginal, topical or rectal delivery, hyoscyamine polistirex or a combination thereof. although oral delivery is used mostly. In addition, conven 50 The present invention includes a soluble chewable tablet tional excipients such as colorants, anti-tack agents, fillers, including a pharmaceutically active drug-resin complex. The plasticizers, pore forming agents, glossing agents, etc. can be pharmaceutically active ingredient is slowly released when added to the present invention. the tablet is chewed. As the tablet is chewed it becomes The present invention provides a taste-masked chewable thixotropic but not fully dissolving for at least 30 seconds, pseudoephedrine and chlorpheniramine pharmaceutical 55 rapidly disintegrating during chewing but preventing the composition. The composition includes a pseudoephedrine release of the ionic drug until after the complex is swallowed resin complex, a chlorpheniramine-resin complex and one or The tablet may contain other conventional ingredients, more amorphous Sugars. The composition also includes a including other fillers, which include water-soluble com compressible, free-flowing, pharmaceutical, taste-masking pressible carbohydrates such as dextrose. Sucrose, mannitol, excipient, wherein the highly compressible, free-flowing 60 sorbitol, maltitol, xylitol, lactose, and mixtures thereof; other pharmaceutical excipient causes disintegration of the tablet conventional dry binders like polyvinyl pyrrolidone and the and liberation of the drug-resin complex in the mouth. In like: Sweeteners such as aspartame, acesulfame potassium, Some instances the resin is polistirex, polyacrilex or a com Sucralose, and Saccharin; and lubricants, such as magnesium bination thereof, and more specifically pseudoephedrine Stearate, Stearic acid, talc, and waxes. The mixture may also polistirex and chlorpheniramine polyacrilex. The amorphous 65 incorporate pharmaceutically acceptable adjuvants, includ sugar may be the commercially available Pharmaburst or ing, for example, preservatives, flavors, antioxidants, Surfac other sugars known to the skilled artisan. However the skilled tants, and coloring agents. US 8,840,924 B2 9 10 When in the form of a chewable tablet components include powder that is comparably sweet to sucrose. The heat of all those Substances which, alone or mixed with one another, Solution of crystalline Xylitol causes a strong cooling sensa behave like chewing gum for at least 5 seconds when chewed, tion in the mouth when the crystals dissolve. Crystalline but begin to disintegrate during this time and are then com xylitol can also change the flavor profiled. Erythritol is an pletely disintegrated and Swallowed with the saliva. The odorless white crystalline powder with a cleanSweet taste that range of Substances include, inter alia, but not exclusively, is similar to sucrose. The heat of solution of crystalline eryth gum arabic, tragacanth, guar gum, Xanthan gum, pectins; but ritol also causes a strong sensory cooling feeling in the mouth also dry syrups, such as, for example, dry glucose syrup like xylitol. Sorbitol is a popular bulk sweetener found in and/or fructose syrup; Soluble cellulose derivatives, such as, numerous food products. In addition to providing Sweetness, for example, sodium carboxymethylcellulose. Dry glucose 10 it is an excellent humectant and texturizing agent. Mannitol is syrup likewise exhibits partly rubber-like behavior on chew a monosaccharide polyol. Both Sorbitol and mannitol are 1ng. generally stable and chemically unreactive. The pharmaceutical composition of the present invention In addition cellulose esters such as cellulose acetate and also includes an orally disintegrable composition having the cellulose acetate butyrate, and cellulose triacetate may be amount of disintegration agent, either effervescent or nonef 15 used as taste masking agents since they do not dissolve in the fervescent or the combination thereof provided sufficient mouth and are tough enough to remain effectively intact Such that the composition provides a pleasant organoleptic during processing and normal chewing in the mouth. sensation in the mouth of the patient. In general, the amount Adsorption of the active ingredient onto the ion exchange of effervescence disintegration agent, noneffervescent disin resin particles to form the active agent-resin complex is a tegration agent or both in accordance with the present inven well-known technique as shown in U.S. Pat. No. 2.990,332 tion should be sufficient to allow for the rapid and complete (relevant portions incorporated herein by reference) and dem disintegration of the composition when orally administered. onstrated in the examples hereinbelow. In general, the active Complete disintegration of the composition does not require ingredient is mixed with an aqueous Suspension of the resin dissolution or disintegration of the microparticies or other and the complex is then dried. Adsorption of the active ingre discrete materials included. 25 dient onto the resin is detected by a change in the pH of the The present invention may contain preservatives to prevent reaction medium. microbial contamination. Examples of preservatives are the In accordance with the present invention the active ingre alkylparabens, particularly methylparaben, propylparaben dient can be any pharmaceutically active material and can and butylparaben. The amount of preservative generally used also include vitamins, minerals, nutritional Supplements and will vary depending upon the preservative selected and may, 30 the like. These can include, without limitation systematically for example, range from about 0.05% to about 15% weight/ distributable pharmaceutically active materials, vitamins, volume of the final composition. The preservative will be minerals, dietary supplements, as well as non-systematically present in an amount from about 0.01% to about 20% weight/ distributable pharmaceutically active materials. Drugs or Volume of the final composition. pharmaceutically active materials may include, without limi In some instances the present invention may include a 35 tation, antacids, analgesics, anti-inflammatories, antipyretics syrup component including glucose syrup, maltodextrin solu antibiotics, antimicrobials, laxatives, anorexics, antihista tion, Swollen gelatin, but also other syrups, such as corn, mines, antiasthmatics, antidiuretics, anti flatuents, antimi Sugar or invert Sugar syrup. Glucose syrup can be completely graine agents, antispasmodics, sedatives, antihyperactives, or partly replaced by other concentrated carbohydrate, Sugar antihypertensives, tranquilizers, decongestants, beta blockers alcohol, gelatin or similar solutions. 40 and combinations thereof. The present invention also includes a tablet formulation In addition, nanoparticulate and microparticulate active that has one or more amorphous Sugars. The skilled artisan agents may be used in the present invention and may include will recognize that many amorphous Sugars may be used. proteins, peptides, nucleotides, anti-obesity drugs, nutraceu Generally, amorphous Sugar signifies a Sugar which is mate ticals, corticosteroids, elastase inhibitors, anti-fungals, rially amorphous or which is capable of becoming amor 45 oncology therapies, anti-emetics, analgesics, cardiovascular phous. In the process of becoming amorphous there may be agents, anti-inflammatory agents, anthelmintics, anti-ar states where a portion is not amorphous. Commercially, rhythmic agents, antibiotics, anticoagulants, antidepressants, amorphous Sugars such as Mannogem EZ and Pharmaburst antidiabetic agents, antiepileptics, antihistamines, antihyper (both available from SPI Pharma, Lewes, Del.) may be used tensive agents, antimuscarinic agents, antimycobacterial to provide fast delivery. 50 agents, antineoplastic agents, immunosuppressants, antithy The skilled artisan will recognize that other amorphous roid agents, antiviral agents, anxiolytics, sedatives, astrin Sugars and combinations of Sugars may be used. Examples of gents, beta-adrenoceptor blocking agents, blood products and amorphous Sugars include glucose, lactose, maltose, Sorbitol, Substitutes, cardiac inotropic agents, contrast media, corti trehalose, lactitol, fructose, polyols and the like. Polyols may costeroids, cough Suppressants, diagnostic agents, diagnostic be used in the present invention and function as an additive, 55 imaging agents, diuretics, dopaminergics, haemostatics, compacting agent, filler, and/or carriers inter alia for active immunological agents, lipid regulating agents, muscle relax pharmaceutical ingredients. Polyols have Sweetening proper ants, parasympathomimetics, parathyroid calcitonin and ties which are comparable to those of Sucrose and many biphosphonates, prostaglandins, radio-pharmaceuticals, sex polyols show a cooling effect, which is felt to be pleasant, hormones, anti-allergic agents, stimulants and anoretics, during the dissolving process. Commonly used polyols 60 sympathomimetics, thyroid agents, vasodilators, and Xan include Xylitol, mannitol, lactitol, isomalt and Sorbitol. thines. Generally, polyols may be used in the present invention as Substrates include a powder that constitutes a finely they have a Sweet taste and can be used to provide a cooling divided (e.g., milled, micronized, nanosized, precipitated) effect in the mouth. Commonly-used polyols include xylitol, form of an active ingredient or additive molecular aggregates mannitol, sorbitol and erythritol. However, the skilled artisan 65 or a compound aggregate of multiple components or a physi will recognize that a variety of polyols and combinations of cal mixture of aggregates of an active ingredient and/or addi polyols may be used. Xylitol is an odorless white crystalline tives. Such substrates may be formed of various materials US 8,840,924 B2 11 12 known in the art, Such as, for example Sugars (e.g., lactose, hydroxybenzoic acids include paraben esters of p-hydroxy Sucrose or dextrose), polysaccharides (e.g., maltodextrin or benzoic acid (e.g., methyl paraben, ethyl paraben, propyl dextrates), starches, cellulosics (e.g., microcrystalline cellu paraben, butyl paraben and benzyl paraben). Salts of drugs lose or microcrystalline cellulose/sodium carboxymethylcel where the anion of the salt is acidic, Such as acetate, hydro lulose), inorganics (e.g., dicalcium phosphate, hydroxyapi chloride, hydrobromide, Sulfate. Succinate, citrate, and the tite, tricalcium phosphate, talc, or titania) and polyols (e.g., like, may be used to produce immediate disintegration and mannitol, xylitol, sorbitol or cyclodextrin). dissolution of the porous particle. Some variation in dosage Flavoring agents that may be used in the present invention will necessarily occur depending on the condition of the include, and are not limited to, natural flavors, natural fruit Subject being treated. The person responsible for administra flavors, artificial flavors, artificial fruit flavors, flavor enhanc 10 tion will, in any event, determine the appropriate dose for the ers or mixtures thereof. Natural flavors, artificial flavors or individual subject. Moreover, for human administration, mixtures thereof include, and are not limited to, mint (e.g., preparations should meet Sterility, pyrogenicity, general peppermint or spearmint), lemon, lime, orange, Strawberry, safety and purity standards as required by FDA Office of menthol, cinnamon, Vanilla, artificial vanilla, chocolate, arti Biologics standards. The interaction of an acidic component ficial chocolate or bubblegum. Natural fruit flavors, artificial 15 with, e.g., a porous particle of for example, calcium hydro fruit flavors or mixtures thereof include, and are not limited gen phosphate, in the presence of water from gastric fluids to, cherry, grape, orange, Strawberry or lemon. Flavor enhanc accelerates dissolution of the particle at a greater rate than ers include, and are not limited to, citric acid. Although fla gastric fluid alone, producing a more rapid and complete Voring agents are generally provided as a minor component of release of the liquid, active agent formulation into the envi the taste masking composition in amounts effective to pro ronment of use. Alternatively, alkaline components or salts of vide a palatable flavor to the liquid pharmaceutical composi drugs may be used if the cation of the salt is alkaline Such as tion, the addition of at least one flavoring agent is preferred; choline may be incorporated into the liquid, active agent and, more preferably, up to two flavoring agents may be formulation to promote rapid and complete dissolution of a employed. A flavoring agent used in the taste masking com porous particle which is soluble or swells at elevated pH. position has a range of from about 0.01 to about 0.15 grams 25 Such a particle may be formed, e.g., of poly(methacrylic per 100 mL. The flavorings are generally utilized in amounts acid-methyl methacrylate) 1:2 available commercially as that will vary depending upon the individual flavor, and may, Eudragit 5100 (Rohm America, Sommerset, N.J.). for example, range in amounts of about 0.01% to about 10% Other additives conventionally used in pharmaceutical by weight/volume of the final composition. compositions may be included, which are well known in the Examples of Sweeteners include Sweetening agents, artifi 30 art. Such additives include, e.g., anti-adherents (e.g., anti cial Sweeteners and dipeptide based Sweeteners, e.g., Sticking agents, glidants, flow promoters, lubricants) Such as monosaccharides, disaccharides and polysaccharides such as talc, magnesium stearate, fumed silica), micronized silica, Xylose, ribose, glucose, mannose, galactose, fructose, dex polyethylene glycols, Surfactants, waxes, Stearic acid, Stearic trose, Sucrose, Sugar, maltose, partially hydrolyzed starch, or acid salts, Stearic acid derivatives, starch, hydrogenated veg corn Syrup Solids and Sugar alcohols such as Sorbitol. Xylitol, 35 etable oils, sodium benzoate, sodium acetate, leucine, PEG mannitol, saccharin salts, i.e., Sodium, or calcium saccharin 4000 and magnesium lauryl sulfate. The present invention salts, cyclamate salts, acesulfam-K, ammonium glycyrrhiz includes purified, hydrated, magnesium silicate (i.e., talc) inate, dipotassium glycyrrhizinate and the free acid form of which is widely used in oral Solid dosage forms as a lubricant saccharin L-aspartylphenylalanine methyl ester and mixtures and diluent. thereof. 40 Pharmaceutical compositions according to the invention Generally, the Sweetener will be present in an amount may also include one or more binding agents, filling agents, corresponding to about 1 to 60% weight/volume of the total lubricating agents, Suspending agents, Sweeteners, flavoring composition, the amount depending in part upon whether agents, preservatives, buffers, wetting agents, disintegrants, other sweeteneringredients are present and the level of sweet effervescent agents, and other excipients. Such components ness desired. Typically Sugar is used it is present from about 45 are known to the skilled artisan. 10% to about 50% w/v of the composition. It will be appre Examples of filling agents include lactose monohydrate, ciated that combinations of Sweeteners can be used. The lactose anhydrous, and various starches. Examples of binding Sweetening agents, when used, may also be used alone or in agents include various celluloses and cross-linked polyvi combination with each other. When an artificial Sweetness nylpyrrolidone, microcrystalline cellulose, microcrystalline enhancer is used it may be present in an amount from about 50 cellulose, and silicized microcrystalline cellulose. Generally, 0.05% to about 15% weight/volume of the final composition. Suitable lubricants, including agents that act on the flowabil The colorants useful in the present invention include pig ity of the powder to be compressed, are colloidal silicon ments such as titanium dioxide, that may be incorporated in dioxide, talc, Stearic acid, magnesium Stearate, calcium Stear amounts of up to about 10% by weight/volume. The colorants ate, and silica gel. may include other dyes Suitable for food, drug and cosmetic 55 Examples of preservatives include Sorbates, and parabens, applications, and known as F.D. & C. dyes and the like. The e.g., potassium Sorbate, methylparaben, propylparaben, ben materials acceptable for the foregoing spectrum of use may be Zoic acid and its salts, other esters of parahydroxybenzoic water-soluble. Illustrative examples include indigoid dye, acid Such as butylparaben, alcohols such as ethyl or benzyl known as F.D. & C. Blue No. 2, which is the disodium salt of alcohol, phenolic compounds Such as phenol, or quarternary 5.5'-indigotindisulfonic acid. Similarly, the dye known as 60 compounds such as benzalkoniurn chloride. In addition Suit F.D. & C. Green No. 1, includes a triphenylmethane dye and able diluents include pharmaceutically acceptable inert fill is the monosodium salt of 4-4-Nethyl-p-sulfobenzylamino) ers, such as microcrystalline cellulose, lactose, dibasic cal diphenylmethylene-1-(N-ethyl-N-p-sulfoniumbenzyl)-2, cium phosphate, saccharides, and/or mixtures of any of the 5-cyclohexadienimine. foregoing. Examples of organic acids for use with the formulations 65 The present invention includes disintegrants which include include, e.g., citric acid, tartaric acid. Succinic acid, malic lightly crosslinked polyvinyl pyrrolidone, corn starch, potato acid, fumaric acid, hydroxybenzoic acid and the like. The starch, maize starch, and modified Starches, croScarmellose US 8,840,924 B2 13 14 Sodium, cross-povidone, Sodium starch glycolate, and mix characteristics. Generally, coolants are compounds that pro tures thereof. Some embodiments of the present invention are vide a physiological cooling effect on the skin or on the in the form of effervescent compositions. Examples of effer mucous membranes of the body, particularly the mucous Vescent agents include an organic acid and a carbonate or membranes of the nose and bronchial tract. For example, bicarbonate. Suitable organic acids include, for example, cit Mentholis well known for its physiological cooling effect on ric, tartaric, malic, fumaric, adipic, Succinic, and alginic acids the skin and mucous membranes of the mouth. The “cooling and anhydrides and acid salts. Suitable carbonates and bicar effect of menthol is a physiological effect due to the direct bonates include, for example, sodium carbonate, sodium action of menthol on the nerve endings of the human body bicarbonate, potassium carbonate, potassium bicarbonate, responsible for the detection of hot or cold and is not due to magnesium carbonate, Sodium glycine carbonate, L-lysine 10 latent heat of evaporation. It is believed that the menthol acts carbonate, and arginine carbonate. Alternatively, only the as a direct stimulus on the cold receptors at the nerve endings, acid component of the effervescent couple may be present which in turn stimulate the central nervous system. In addi invention. tion, menthol is a major constituent of oil of peppermint and For certain actives it may be useful to provide buffering may function as a flavoring as well. Since many of the physi agents, where the acid is a pharmaceutically acceptable acid, 15 ological cooling agents do not have their own perceptible Such as hydrochloric acid, hydrobromic acid, hydriodic acid, flavor they can be combined with other types of flavors to Sulfuric acid, nitric acid, boric acid, phosphoric acid, acetic offer new and unique advantages. acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic Physiological cooling agents that may be used in the acid, amino acids, ascorbic acid, benzoic acid, boric acid, present invention include menthol, menthone glycerol ketal, butyric acid, carbonic acid, citric acid, fatty acids, formic menthyl lactate, N-ethyl-p-menthane-3-carboxamide, 3-1- acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, menthoxypropane-1,2...diol, 3-substituted-P-menthanes, isoascorbic acid, lactic acid, maleic acid, methanesulfonic N-substituted-P-menthane-3-carboxamides and 3-1-men acid, oxalic acid, para-bromophenylsulfonic acid, propionic thoxypropane-1,2-diol. 3-1-menthoxypropane-1,2-diol, a acid, p-toluenesulfonic acid, salicylic acid, Stearic acid, suc ketal combined with another coolant (e.g., menthol or car cinic acid, tannic acid, tartaric acid, thioglycolic acid, tolu 25 boxamides), physiological cooling agents and reduced men enesulfonic acid and uric acid, and where the base is a phar thol, menthone ketals, menthone glycerol ketals, cyclodextrin maceutically acceptable base. Such as an amino acid, an complex with physiological cooling agents, ketoesters of amino acid ester, ammonium hydroxide, potassium hydrox menthol, Sulphoxides and Sulphones, acyclic carboxamides, ide, Sodium hydroxide, Sodium hydrogen carbonate, alumi menthyl lactate, cyclohexanamides, carbonic acids having num hydroxide, calcium carbonate, magnesium hydroxide, 30 free polar groups, acyclic secondary and tertiary alkanols, magnesium aluminum silicate, synthetic aluminum silicate, menthyl Succinate and carboxamides, alpha-oxy(OXo)mer synthetic hydrotalcite, magnesium aluminum hydroxide, captain alkanes, acyclic sulphonamides and sulphinamides, diisopropylethylamine, ethanolamine, ethylenediamine, tri Substituted p-menthane-3-carboxamides, Substituted cyclo ethanolamine, triethylamine, triisopropanolamine, or a salt of hexanamides, alkyl Substituted alicyclic carboxylic acids, a pharmaceutically acceptable cation and acetic acid, acrylic 35 alkyl substituted alicyclic esters, alkyl substituted alicyclic acid, adipic acid, alginic acid, alkanesulfonic acid, an amino amides, 3-substituted p-menthanes, p-menthane-3-carboxy acid, ascorbic acid, benzoic acid, boric acid, butyric acid, lates, N-acetylglycine menthyl ester, L-menthyl-3-hydroxy carbonic acid, citric acid, a fatty acid, formic acid, fumaric butyrate, 2-isopropenyl-5-methylcyclohexanol, bicyclic acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acids, esters, amides and Substituted menthanols, trialkyl acid, lactic acid, maleic acid, methanesulfonic acid, oxalic 40 Substituted cyclohexane carboxamides, cyclic and acyclic acid, para-bromophenylsulfonic acid, propionic acid, p-tolu amides, ureas and Sulphonamides, p-menthane carboxamide enesulfonic acid, salicylic acid, Stearic acid, Succinic acid, physiological cooling agent with menthol, 3-I-menthoxypro tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic pane-1,2-diol. N-Substituted p-menthane carboxamides and acid, and uric acid. The buffer include acids and their base menthol, cyclohexanol derivatives, Substituted p-menthanes, salts for example, citric acid (e.g., citric acid anhydrous), 45 Substituted p-menthane-carboxamides (e.g., N-ethyl-p-men tartaric acid, malic acid, phosphoric acid and the like and their thane-3-carboxamide), acyclic darboxamides, Substituted respective salts. cyclohexanamides, Substituted cyclohexane carboxamides, The present invention may also include one or more bind Substituted ureas and Sulphonamides, and Substituted men ers. The choice of binder for a given application may also be thanols, hydroxymethyl and hydroxyethyl derivatives of determined readily by those skilled in the art. Generally, the 50 p-menthane, menthyl Succinate, 2-mercapto-cyclo-de binder must be capable of wetting the surfaces of the particle canone, 2-isopropanyl-5-methylcyclohexanol, hydroxycar being pelletized or granulated. In general, binders must have boxylic acids with 2-6 carbon atoms, menthone glycerol ket Sufficient wet strength to allow agglomerates to be handled als, 3-I-menthoxypropane-1,2-dial, menthyl lactate, and sufficient dry strength to make them suitable for their substituted p-menthane carboxamides (PMC), N-ethyl-p- intended purposes. Each process, however, makes use of a 55 menthane-3-carboxamide, acyclic carboxamides (AC), N-2, different system of forces and may require a different 3-trimethyl-2-isopropyl butanamide, N-ethyl-2,3-dimethyl agglomerate strength. The final selection of the binder is 2-isopropyl butanamide, N, 2,3-trimethyl-2-isopropyl made generally based on the type of equipment used. Factors butanamide, menthone glycerol ketal (MGK), menthyl lac that affect the equipment and binder choices include: the size tate (ML), menthyl succinate (MS), 3-I-menthoxypropane-1, and size distribution of pellets, bulk density, strength and flow 60 2-diol (TCA). Physiological cooling agents may generally be properties. Other factors that affect the performance of the of the chemical classification of ketone, hemiketal, ketal, pellets, which may be adjusted by one skilled in the art by the acetal, or hemiacetal. inclusion of additives, choice of equipment and processing Stearic acid is commonly used in the pharmaceutical conditions. industry primarily as a lubricant for tablets and capsules. It is The present invention may also include one or more cool 65 typically used in a concentration of 1% to 10% when used as ants that will contribute a cooling sensation to products in a tablet lubricant. Stearic acid is described as a mixture of which it is found without the unwanted harshness or flavor Stearic acid and palmitic acid. The content of Stearic acid is US 8,840,924 B2 15 16 not less than about 10% and the sum of the two acids is not Stearate, sodium chloride, potassium chloride, citric acid, less than about 90.0%. Stearic acid is used as an emulsifying spray-dried lactose, hydrolyzed Starches, directly compress agent; solubilizing agent; tablet and capsule lubricant. The ible starch, microcrystalline cellulose, cellulosics, sorbitol, purpose in this formulation is that of a lubricant of the Sucrose. Sucrose-based materials, calcium sulfate, dibasic gauifenesin so that an adequate plug can be produced and 5 calcium phosphate and dextrose). Yet other additives may delivered through the dosing disk without excessive wear. include disintegrants or Super disintegrants; hydrogen bond Suitable excipients are those used commonly to facilitate ing agents, such as magnesium oxide; flavorants or desensi the processes involving the preparation of the Solid carrier, the tizers. encapsulation coating, or the pharmaceutical dosage form. The present invention may also include one or more surface These processes include agglomeration, air Suspension chill 10 stabilizer selected from the group consisting of cetyl pyri ing, air Suspension drying, balling, coacervation, comminu dinium chloride, gelatin, casein, phosphatides, dextran, glyc tion, compression, pelletization, cryopelletization, extrusion, erol, gum acacia, cholesterol, tragacanth, Stearic acid, Stearic granulation, homogenization, inclusion complexation, lyo acid esters and salts, calcium Stearate, glycerol monostearate, philization, nanoencapsulation, melting, mixing, molding, cetostearyl alcohol, cetomacrogol emulsifying wax, Sorbitan pan coating, solvent dehydration, Sonication, spheronization, 15 esters, polyoxyethylene alkyl ethers, polyoxyethylene castor spray chilling, spray congealing, spray drying, or other pro oil derivatives, polyoxyethylene sorbitan fatty acid esters, cesses known in the art. The excipients may also be pre polyethylene glycols, dodecyltrimethylammonium bromide, coated or encapsulated, as are well known in the art. polyoxyethylene Stearates, colloidal silicon dioxide, phos The excipient in the form of a hydrate may be selected from phates, Sodium dodecylsulfate, carboxymethylcellulose cal organic compounds such as dextrose monohydrate, malto cium, hydroxypropyl celluloses, hydroxypropyl methylcellu dextrin, lactose monohydrate, dextrin, and citric acid mono lose, carboxymethylcellulose Sodium, methylcell ulose, hydrate, as well as inorganic compounds including dibasic hydroxyethylcellulose, hydroxypropyl methyl-cellulose calcium phosphate dihydrate, dibasic sodium phosphate phthalate, noncrystalline cellulose, magnesium aluminum dihydrate, dibasic sodium phosphate heptahydrate, dibasic silicate, triethanolamine, polyvinyl alcohol, polyvinylpyr Sodium phosphate dodecahydrate, monobasic sodium phos 25 rolidone, 4-(1,1,3,3-tetramethylbutyl)-phenol polymer with phate monohydrate, and monobasic sodium phosphate dihy ethylene oxide and formaldehyde, poloxamers, poloxamines, drate. Preferably, the excipient in the form of a hydrate is an a charged phospholipid, dimyristoyl phophatidyl glycerol, organic compound, more preferably dextrose monohydrate. dioctylsulfoSuccinate, dialkylesters of Sodium SulfoSuccinic The present invention may include calcium Stearate and/or acid, Sodium lauryl Sulfate, alkyl aryl polyether Sulfonates, magnesium Stearate which are primarily used in pharmaceu 30 mixtures of Sucrose Stearate and Sucrose distearate, triblock tical formulations as a lubricant in tablet and capsule manu copolymers of the structure: -(-PEO)-(-PBO-)-(-PEO-)-. facture. Calcium stearate has good anti-adherent and lubri p-sononylphenoxypoly-(glycidol), decanoyl-N-methylglu cant properties. Maltodextrin is used in tablet formulations as camide; n-decyl B-D-glucopyranoside, n-decyl B-D-malto a binder and diluent in both direct compression and wet pyranoside, n-dodecyl B-D-glucopyranoside, n-dodecyl B-D- granulation process. Maltodextrinappears to have no adverse 35 maltoside, heptanoyl-N-methylglucamide, n-heptyl-B-D- effects on the rate of tablet dissolution. As a binder it is glucopyranoside, n-heptyl B-D-thioducoside, n-hexyl B-D- typically used in concentrations of 1% to 25%. glucopyranoside, nonanoyl-N-methylglucamide, n-noyl The pharmaceutical compositions of the present invention B-D-glucopyranoside, octanoyl-N-methylglucamide, n-oc may include optionally one or more solubilizers, i.e., addi tyl-B-D-glucopyranoside. octyl B-D-thioglucopyranoside, tives to increase the solubility of the pharmaceutical active 40 lysozyme, a PEG derivatized phospholipid, PEG derivatized ingredient or other composition components in the Solid car cholesterol, a PEG derivatized cholesterol derivative, PEG rier. It has been recognized by the present inventors that derivatized vitamin A, PEG derivatized vitamin E, and ran guaifenesin, in fact, acts as a solubilizer for phenylephrine, dom copolymers of vinyl acetate and vinyl pyrrolidone, and is used as such in the examples provided herein. Other biopolymers, polysaccharides, cellulosics, cationic lipids, solubilizers are known in the art. Mixtures of solubilizers are 45 benzalkonium chloride, Sulfonium compounds, phospho also within the scope of the invention and are readily available nium compounds, quartemary ammonium compounds, ben from standard commercial sources. Zyl-di(2-chloroethyl)ethylammonium bromide, coconut tri The amount of solubilizer that may be included in compo methyl ammonium chloride, coconut trimethyl ammonium sitions of the present invention is not particularly limited. Of bromide, coconut methyl dihydroxyethyl ammonium chlo course, when Such compositions are administered to a patient, 50 ride, coconut methyl dihydroxyethyl ammonium bromide, the amount of a given solubilizer is limited to a bioacceptable decyl triethyl ammonium chloride, decyl dimethyl hydroxy amount, which is readily determined by one of skill in the art. ethyl ammonium chloride, decyl dimethyl hydroxyethyl In some circumstances, it may be advantageous to include ammonium chloride bromide, C2-s dimethyl hydroxyethyl amounts of solubilizers far in excess of bioacceptable ammonium chloride, C-dimethyl hydroxyethyl ammo amounts, for example, to maximize the concentration of 55 nium chloride bromide, coconut dimethyl hydroxyethyl active ingredient, with excess solubilizer removed prior to ammonium chloride, coconut dimethylhydroxyethyl ammo providing the composition to a patient using conventional nium bromide, myristyl trimethyl ammonium methyl Sul techniques, such as distillation or evaporation. phate, lauryl dimethyl benzyl ammonium chloride, lauryl In some formulations additives may also include chelating dimethyl benzyl ammonium bromide, lauryl dimethyl agents (e.g., EDTA and EDTA salts); colorants or opaquants 60 (ethenoxy)4 ammonium chloride, lauryl dimethyl (e.g., titanium dioxide, food dyes, lakes, natural vegetable (ethenoxy)4 ammonium bromide, N-alkyl (Cs)dimethyl colorants, iron oxides, silicates, Sulfates, magnesium hydrox benzyl ammonium chloride, N-alkyl (Cs)dimethyl-ben ide and aluminum hydroxide); coolants (e.g., trichloroethane, Zyl ammonium chloride, N-tetradecylidmethylbenzyl ammo trichloroethylene, dichloromethane, fluorotrichlo nium chloride monohydrate, dimethyl didecyl ammonium romethane); cryoprotectants (e.g., trehelose, phosphates, cit 65 chloride, N-alkyl and (C-4) dimethyl 1-napthylmethyl ric acid, tartaric acid, gelatin, dextran and mannitol); and ammonium chloride, trimethylammonium halide, alkyl-trim diluents or fillers (e.g., lactose, mannitol, talc, magnesium ethylammonium salts, dialkyl-dimethylammonium salts, lau US 8,840,924 B2 17 18 ryl trimethyl ammonium chloride, ethoxylated alkyami moistened with an inert liquid diluent. The tablets may be doalkyldialkylammonium salt, an ethoxylated trialkyl optionally coated or scored and may be formulated so as to ammonium salt, dialkylbenzene dialkylammonium chloride, provide a slow or controlled release of the therapeutic ingre N-diclecyldimethyl ammonium chloride, N-tetradecyldim dient therein. ethylbenzyl ammonium, chloride monohydrate, N-alkyl (C2 14) dimethyl 1-naphthylmethyl ammonium chloride, dode The tablet may be made in any manner, and a variety of cyldimethylbenzyl ammonium chloride, dialkyl tableting methods are known in the art. Conventional meth benzenealkyl ammonium chloride, lauryl trimethyl ammo ods for tablet production include direct compression (“dry nium chloride, alkylbenzyl methyl ammonium chloride, alkyl blending'), dry granulation followed by compression, and benzyl dimethyl ammonium bromide, C2 trimethyl ammo 10 wet granulation followed by drying and compression. Other nium bromides, Cs trimethyl ammonium bromides, C7 tri methods include the use of compacting roller technology, methyl ammonium bromides, dodecylbenzyl triethyl ammo e.g., a chilsonator (e.g., a dry granulation/roll compactor nium chloride, poly-diallyldimethylammonium chloride, roller press system), drop roller, molding, casting, or extru dimethyl ammonium chlorides, alkyldimethylammonium sion technologies. All of these methods are well known in the halogenides, tricetyl methyl ammonium chloride, decyltrim 15 art. The tablets are formed by the direct compression method, ethylammonium bromide, dodecyltriethylammonium bro which involves directly compacting a blend of the active mide, tetradecyltrimethylammonium bromide, methyl trio ingredient, the excipient in the form of a hydrate, the water ctylammonium chloride, tetrabutylammonium bromide, Swellable excipient, and any other appropriate optional ingre benzyl trirnethylammonium bromide, choline esters, benza dients. After blending, a pre-determined volume of particles Ikonium chloride, Stearalkonium chloride compounds, cetyl is filled into a die cavity of a rotary tablet press, which con pyridinium bromide, cetyl pyridinium chloride, halide salts tinuously rotates as part of a “die table' from the filling of quaternized polyoxyethylalkylamines, alkyl pyridinium position to a compaction position. The particles are com salts; amines, amine salts, amine oxides, imide azolinium pacted between an upper punch and a lower punch to an salts, protonated quaternary acrylamides, methylated quater ejection position, at which the resulting tablet is pushed from nary polymers, cationic guar, polymethylmethacrylate trim 25 ethylammonium bromide, polyvinylpyrrolidone-2-dimethy the die cavity by the lower punch and guided to an ejection laminoethyl methacrylate dimethyl Sulfate, chute by a stationary “take-off bar. hexadecyltrimethyl ammonium bromide, poly (2-methacry Two examples of the present invention include a chewable loxyethyltrimethylammonium bromide), poly(N-vinyl pyr tablet with the following formulations: rolidone/2-dimethylaminoethyl methacrylate) dimethylsul 30 phate quarternary and poly(2- methylacryloxyamidopropyltrimethylammonium chloride). Example I Pelletizers are generally classified based on the angle of their axis as a horizontal drum or an inclined dish pelletizer. Rotary fluidized granulators may also be used for pelletiza 35 First active ingredient polistirex 100.00 mg tion. A standard fluidized drier bowl may be replaced with a Second active ingredient polistirex 15.00 mg rotating plate as an air distributor. For granulation, a binder Pharamaburst 170.00 mg liquid is sprayed from via one or two binary nozzles located Sorbitol 100.00 mg axially to the rotational movement of the powder bed. The Sweetener 25.00 mg granulation results in rounding of the granules to approxi 40 Xylisorb 30.00 mg mately spherical pellets. Such balling or agitation techniques Citric acid 10.00 mg are generally influenced by operating conditions, e.g., the Flavor 7.50 mg bridging/binding liquid requirements, the residence time of Dye 2.50 mg the material in the pelletizer, the speed and angle of inclina Talc 40.00 mg tion of the pelletizer, the amount of material fed to the pellet 45 Steric acid 10.00 mg izer and the choice and levels of binder, etc. Those skilled in the art may adjust readily such factors to produce a satisfac tory product. A pelletization process typically involves preparing a mol Example II ten solution of the composition of the solid carrier or a dis 50 persion of the composition of the solid carrier solubilized or Suspended in an aqueous medium, an organic solvent, a supercritical fluid, or a mixture thereof. Such solution or Pseudoephedrine polistrex 99.70 mg dispersion is then passed through a certain opening to achieve Chlorpheniramine polyacrilex 14.70 mg 55 Pharamaburst 170.00 mg the desired shape, size, and other properties. Similarly, appro Sorbitol 100.00 mg priate drying processes may be used to control the level of the Aspertame 25.00 mg residual dispersing medium, if necessary. The processes Xylisorb 30.00 mg described above, the combination of the processes, or the Citric acid 10.00 mg Grape Flavor 7.50 mg modification of the processes are well know in the art. Purple Lake Blend 2.50 mg A tablet may be made by compression or molding, option 60 Talc 40.00 mg ally with one or more accessory ingredients. Compressed Steric acid 10.00 mg tablets may be prepared by compressing, in a Suitable machine, the therapeutic ingredient in a free-flowing form Such as a powder or granules, optionally mixed with a binder, Below is a list of actual assay results for one example of the lubricant, inert diluent, preservative, Surface therapeutic or 65 present invention with the composition listed as formula II dispersing agent. Molded tablets may be made by molding, in above. The dissolution profile for the release of pseudoephe a suitable machine, a mixture of the powdered compound drine and chlorpheniramine are shown in Table 1, below. US 8,840,924 B2 20 TABLE 1. 85.2% respectively. The dissolution profile also shows that 40.1% of the chlorpheniramine is released within 30 minutes. 30 min (%) 1 Hr (%) 3 Hr (%) 8 Hr (%) The release of chlorpheniramine at 1 hour is about 45.1%. Chlorpheniramine 35.1 42.7 S1.6 60.8 The release profile after 3 hours and 8 hours demonstrate a Pseudoephedrine 27.6 37.8 59.4 82.O 5 release of 53.3% and 62.1% respectively. In addition the composition may be in the form of a cap Based on assay and dissolution profile 35.1% of the chlo sule. Below is a list of actual assay results for one example of rpheniramine is released within 30 minutes. The release of the present invention when in the form of a capsule. The dissolution profile for the release of pseudoephedrine and chlorpheniramine at 1 hour is about 42.7%. The release pro 10 file after 3 hours and 8 hours demonstrate a release of 51.6% chlorpheniramine are shown in Table 4, below. and 60.8% respectively. The dissolution profile also shows that 26.7% the pseudoephedrine is released within 30 min TABLE 4 utes. The release of pseudoephedrine at 1 hour is about Capsules 90 min (%) 3 Hr (%) 6 Hr (%) 12 Hr (%) 37.8%. The release profile after 3 hours and 8 hours demon- 15 Pseudoephedrine 34.8 54.1 75.4 91.7 strate a release of 59.4% and 82.0% respectively. Chlorpheniramine 21.9 35.4 55.2 78.6 Example III Based on assay and dissolution profile of the capsule 34.8% of the pseudoephedrine is released within 90 minutes. The release of pseudoephedrine at 3 hour is about 54.1%. The Pseudoephedrine polistrex 102.92 mg Chlorpheniramine polyacrilex 15.11 mg release profile after 6 hours and 12 hours demonstrate a Pharamaburst 170.00 mg release of 75.4% and 91.7% respectively. The dissolution Sorbitol 86.97 mg profile also shows that 21.9% of the chlorpheniramine is Aspertame 25.00 mg 25 released within 90 minutes. The release of chlorpheniramine Xylisorb 30.00 mg Citric acid 10.00 mg at 3 hour is about 35.4%. The release profile after 6 hours and Grape Flavor 7.50 mg 12 hours demonstrate a release of 55.2% and 78.6% respec Purple Lake Blend 2.50 mg tively. Talc 40.00 mg Generally, sorbitol is highly compressible and binds other Steric acid 10.00 mg 30 tablet ingredients and may be used in pharmaceutical tablets, powders, and Sachets. It may be used in direct compression Below is a list of assay results for one example of the tableting have particle size distributions that make them free present invention with the composition listed as formula II flowing. The particle size is controlled to optimize the flow above. The dissolution profile for the release of pseudoephe characteristics of the granulations in modern tablet presses. drine and chlorpheniramine are shown in Table 2, below. 35 Sorbitol increases the strength and integrity of a pharmaceu tical tablet. The skill artisan will recognize that other sub TABLE 2 stances may be used in place of Sorbitol or in addition to sorbitol. 30 min (%) 1 Hr (%) 3 Hr (%) 8 Hr (%) Example IV Chlorpheniramine 36.4 42.1 S1.O 60.7 40 Pseudoephedrine 27.0 36.3 53.0 78.4

Based on assay and dissolution profile 36.4% of the chlo Pseudoephedrine polistrex 102.92 mg rpheniramine is released within 30 minutes. The release of Chlorpheniramine polyacrilex 15.11 mg 45 Pharamaburst 170.00 mg chlorpheniramine at 1 hour is about 42.1%. The release pro Sorbitol 86.97 mg file after 3 hours and 8 hours demonstrate a release of 51.0% Aspertame 25.00 mg and 60.7% respectively. The dissolution profile also shows Xylisorb 30.00 mg that 27.0% of the pseudoephedrine is released within 30 Citric acid 10.00 mg Grape Flavor 7.50 mg minutes. The release of pseudoephedrine at 1 hour is about 50 Purple Lake Blend 2.50 mg 36.3%. The release profile after 3 hours and 8 hours demon Talc 40.00 mg strate a release of 53.0% and 78.4% respectively. Steric acid 10.00 mg Below is a list of actual assay results for one example of the present invention with the composition listed as formula II above. The dissolution profile for the release of pseudoephe 55 Example V drine and chlorpheniramine are shown in Table 3, below.

TABLE 3 Active ingredient polistirex 0.33 mg 30 min (%) 1 Hr (%) 3 Hr (%) 8 Hr (%) Amorphous Sugar 150.00 mg 60 Excipient/binder 10.00 mg Chlorpheniramine 40.1 45.1 53.3 62.1 Sweetener 5.00 mg Pseudoephedrine 29.2 39.7 61.2 85.2 Coolant 2.67 mg Flavor 6.00 mg Dye 0.50 mg Based on assay and dissolution profile 29.2% of the pseu Talc 30.00 mg doephedrine is released within 30 minutes. The release of 65 Steric acid 5.00 mg pseudoephedrine at 1 hour is about 39.7%. The release profile after 3 hours and 8 hours demonstrate a release of 61.2% and US 8,840,924 B2 21 22 Example VI Other carriers for use with the present invention include, e.g., starch, modified Starch, and Starch derivatives, gums, including but not limited to Xanthan gum, alginic acid, other alginates, benitonite, Veegum, agar, guar, locust bean gum, Hyoscyamine polistirex 0.33 mg Pharmaburst 150.00 mg gum arabic, quince psyllium, flaxseed, okragum, arabinogla Povidone 10.00 mg ctin, pectin, tragacanth, Scleroglucan, dextran, amylose, amy Aspertame 5.00 mg lopectin, dextrin, etc., cross-linked polyvinylpyrrolidone, Coolant 2.67 mg ion-exchange resins, such as potassium polymethacrylate, Peppermint Flavor 6.00 mg carrageenan (and derivatives), gum karaya, biosynthetic gum, Lake Blend Lt Green 0.50 mg 10 Talc 30.00 mg etc. Other useful polymers include: polycarbonates (linear Steric acid 5.00 mg polyesters of carbonic acid); microporous materials (bisphe nol, a microporous poly(vinyl chloride), micro-porous polya mides, microporous modacrylic copolymers, microporous Example VII styrene-acrylic and its copolymers); porous polysulfones, 15 halogenated poly(vinylidene), polychloroethers, acetal poly mers, polyesters prepared by esterification of a dicarboxylic acid or anhydride with an alkylene polyol, poly(alkylene Hyoscyamine polistirex 0.33 mg Sulfides), phenolics, polyesters, asymmetric porous poly Mannogem TM EZ 150.00 mg Povidone 10.00 mg mers, cross-linked olefin polymers, hydrophilic microporous Aspertame 5.00 mg homopolymers, copolymers or interpolymers having a Coolant 2.67 mg reduced bulk density, and other similar materials, poly(ure Peppermint Flavor 6.00 mg Lake Blend Lt Green 0.50 mg thane), cross-linked chain-extended poly(urethane), poly(im Talc 30.00 mg ides), poly(benzimidazoles), collodion, regenerated proteins, Steric acid 5.00 mg 25 semi-solid cross-linked poly(vinylpyrrolidone). Additional additives and their levels, and selection of a primary coating material or materials will depend on the When formulated with microparticles or nanoparticles, the following properties: resistance to dissolution and disintegra one or more actives the release profile can easily be adapted tion in the stomach; impermeability to gastric fluids and drug/ by adding, e.g., a hard or softgelatin coating, a starch coating, 30 carrier/enzyme while in the stomach; ability to dissolve or a resin or polymer coating and/or a cellulosic coating. disintegrate rapidly at the target intestine site; physical and Although not limited to microparticles or nanoparticles such chemical stability during storage; non-toxicity; easy applica dosage forms may be further coated with, for example, a seal tion as a coating (Substrate friendly); and economical practi coating, an enteric coating, an extended release coating, or a cality. targeted delayed release coating. The term “enteric coating 35 The one or more active agents that are formulated in a as used herein relates to a mixture of pharmaceutically self-stable manner using the present invention may include a acceptable excipients that is applied to, combined with, wide variety of uses, not just the traditional pharmaceutical mixed with or otherwise added to the carrier or composition. agents. Those skilled in the art will appreciate that any of The coating may be applied to an active that is compressed, these compounds may be used in the form of their pharma molded or extruded and may also include: gelatin, and/or 40 ceutically acceptable salt forms, e.g., carboxylic acids, with pellets, beads, granules or particles of the carrier or compo counter-ions, e.g., potassium, Sodium, calcium; as ionic com sition. The coating may be applied through an aqueous dis binations with, e.g., resins, polymers, beads, matrices; with persion or after dissolving in appropriate solvent. The carrier Sugars or Sugar derivatives, e.g., malate, tannate; amino acids, may or may not be fully or partially biodegradable. lipids, oils or combinations, mixtures and the like. In some Carriers for use with the present invention include perme 45 embodiments, the present inventors have found that certain able and semipermeable matrices or polymers that control the actives may be provided with two different salts, each of release characteristics of the formulation. Such polymers which may have a different solubility and/or release profile include, for example, cellulose acylates, acetates, and other under, e.g., physiologic conditions. In fact, liquid formulation semi-permeable polymers as well as the selectively perme of present invention includes combinations of one or more of able polymers formed by the coprecipitation of a polycation 50 the following: immediate release, pulsatile release, controlled and a polyanioni. The carrier of the compositions of the release, extended release, delayed release, targeted release, or present invention may be a powder or a multiparticulate, Such targeted delayed release. as a granule, a pellet, a bead, a spherule, a beadlet, a micro Some examples of active ingredients suitable for use in the capsule, a millisphere, a nanocapsule, a nanosphere, a micro pharmaceutical formulations and methods of the present sphere, a platelet, a minitablet, a tablet or a capsule. A carrier 55 invention include hydrophilic, lipophilic, amphiphilic or may be a finely divided (e.g., milled, micronized, nanosized, hydrophobic, and that can be solubilized, dispersed, or par precipitated) form of a matrix on which the active ingredient tially solubilized and dispersed, on or about a earlier. For is disposed. Such matrix may be formed of various materials example, the following example may be used for the follow known in the art, Such as, for example: Sugars, such as lactose, ing active agents: Sucrose or dextrose; polysaccharides, such as maltodextrin or 60 dextrates; starches; cellulosics, such as microcrystalline cel Example VIII lulose or microcrystalline cellulose/sodium carboxymethyl cellulose; inorganics, such as dicalcium phosphate, hydroxyapitite, tricalcium phosphate, talc, or titania; and Active Agent-polistirex 0.33 mg polyols. Such as mannitol. Xylitol, Sorbitol or cyclodextrin. It 65 Mannogem TM EZ 150.00 mg should be emphasized that a substrate need not be a solid Povidone 10.00 mg material, although often it will be a solid. US 8,840,924 B2 23 24 -continued profen, fluvastatin, fosphenytoin, froVatriptan, furazolidone, gabapentin, gemfibrozil, glibenclamide, glipizide, glyburide, Aspertame 5.00 mg glimepiride, griseofulvin, halofantrine, ibuprofen, irbesartan, Coolant 2.67 mg Peppermint Flavor 6.00 mg irinotecan, isosorbide dinitrate, isotretinoin, itraconazole, Lake Blend Lt Green 0.50 mg ivermectin, ketoconazole, ketorolac, lamotrigine, lanSopra Talc 30.00 mg Zole, leflunomide, lisinopril, loperamide, loratadine, lovasta Steric acid 5.00 mg tin, L-thrynoxine, lutein, lycopene, medroxyprogesterone, mifepristone, mefloquine, megestrol acetate, methadone, The active agent-carrier combination may be coated fur methoXSalen, metronidazole, miconazole, midazolam, migli ther to encapsulate the agent-carrier combination. Alterna 10 tol, minoxidil, mitoxantrone, montelukast, nabumetone, nal tively, an active ingredient may also be provided separately buphine, naratriptan, nelfinavir, nifedipine, nilsolidipine, nilutanide, nitrofurantoin, nizatidine, omeprazole, oprevel from the Solid pharmaceutical composition, such as for co kin, oestradiol, oxaprozin, paclitaxel, paracalcitol, paroxet administration. Such active ingredients can be any compound ine, pentazocine, pioglitaZone, pizofetin, pravastatin, pred or mixture of compounds having therapeutic or other value 15 nisolone, probucol, progesterone, pseudoephedrine, when administered to an animal, particularly to a mammal, pyridostigmine, rabeprazole, raloxifene, rofecoxib, repaglin Such as drugs, nutrients, coSmaceuticals, nutraceuticals, diag ide, rifabutine, rifapentine, rimexolone, ritanovir, rizatriptan, nostic agents, nutritional agents, and the like. The active rosiglitaZone, saquinavir, Sertraline, Sibutramine, Sildenafil agents of the present invention may be found in their native citrate, simvastatin, sirolimus, spironolactone, Sumatriptan, state; however, they will generally be provided in the form of tacrine, tacrolimus, tamoxifen, tamsulosin, targretin, tazaro a salt. The active agents listed below include their isomers, tene, telmisartan, teniposide, terbinafine, teraZosin, tetrahy analogs and derivatives. drocannabinol, tiagabine, ticlopidine, tirofibran, tizanidine, In one embodiment, the active ingredient agent is hydro topiramate, topotecan, toremifene, tramadol, tretinoin, trogli phobic. Hydrophobic active ingredients are compounds with taZone, trovafloxacin, ubidecarenone, Valsartan, Venlafaxine, little or no water solubility. Intrinsic water solubilities for 25 Verteporfin, vigabatrin, vitaminA, vitamin D. Vitamin E. Vita hydrophobic active ingredients are generally less than about min K. Zafirlukast, Zileuton, Zolmitriptan, Zolpidem, and 15% by weight. Suitable hydrophobic active ingredients are Zopiclone. Of course, salts, isomers and derivatives of the not limited by therapeutic category, and can be, for example, above-listed hydrophobic active ingredients may also be analgesics, anti-inflammatory agents, antihelmimthics, anti used, as well combinations and mixtures thereof. arrhythmic agents, anti-bacterial agents, anti-viral agents, 30 In other embodiments, the active ingredient is hydrophilic, anti-coagulants, anti-depressants, anti-diabetics, anti-epilep however, combination of hydrophilic, hydrophobic and non tics, anti-fungal agents, anti-gout agents, anti-hypertensive polar agents may also be used. The water solubility for hydro agents, anti-malariale, anti-migraine agents, anti-muscarinic philic active ingredients is generally greater than about 0.1% agents, anti-neoplastic agents, erectile dysfunction improve by weight, and typically greater than about 1% by weight. ment agents, immunosuppressants, anti-protozoal agents, 35 Suitable hydrophilic active ingredients include: analgesics, anti-thyroid agents, anxiolytic agents, sedatives, hypnotics, anti-inflammatory agents, antihelminthics, anti-arrhythmic neuroleptics. B-Blockers, cardiac inotropic agents, corticos agents, anti-bacterial agents, anti-viral agents, anti-coagu teroids, diuretics, anti-parkinsonian agents, gastro-intestinal lants, anti-depressants, anti-diabetics, anti-epileptics, anti agents, histamine receptor antagonists, keratolytics, lipid fungal agents, anti-gout agents, anti-hypertensive agents, regulating agents, anti-anginal agents, cox-2 inhibitors, leu 40 anti-malarials, anti-migraine agents, anti-muscarinic agents, kotriene inhibitors, macrollides, muscle relaxants, nutritional anti-neoplastic agents, erectile dysfunction improvement agents, opioid analgesics, protease inhibitors, sex hormones, agents, immunosuppressants, anti-protozoal agents, anti-thy stimulants, muscle relaxants, anti-osteoporosis agents, anti roid agents, anxiolytic agents, sedatives, hypnotics, neurolep obesity agents, cognition enhancers, anti-urinary inconti tics, beta.-Blockers, cardiac inotropic agents, corticoster nence agents, nutritional oils, anti-benign prostate hypertro 45 oids, diuretics, anti-parkinsonian agents, gastro-intestinal phy agents, essential fatty acids, non-essential fatty acids, and agents, histamine receptor antagonists, keratolytics, lipid mixtures thereof. Salts, isomers and derivatives of the above regulating agents, anti-anginal agents, cox-2 inhibitors, leu listed hydrophobic active ingredients may also be used, as kotriene inhibitors, macrollides, muscle relaxants, nutritional well as combinations and mixtures thereof. agents, opioid analgesics, protease inhibitors, sex hormones, Other examples of suitable hydrophobic active ingredients 50 stimulants, muscle relaxants, anti-osteoporosis agents, anti include: acetretin, albendazole, albuterol, aminoglutethim obesity agents, cognition enhancers, anti-urinary inconti ide, amiodarone, amlodipine, amphetamine, amphotericin B, nence agents, nutritional oils, anti-benign prostate hypertro atorvastatin, atovaquone, azithromycin, baclofen, beclom phy agents, essential fatty acids, non-essential fatty acids, and ethasone, benezepril, benzonatate, betamethasone, bicalut mixtures thereof anide, budesonide, bupropion, buSulfan, butenafine, calcife 55 Other hydrophilic active ingredients include: a cytokine, a diol, calcipotriene, calcitriol, camptothecin, candesartan, peptidomimetic, a peptide, a protein, a toxoid, a serum, an capsaicin, carbameZepine, carotenes, celecoxib, cerivastatin, antibody, a vaccine, a nucleoside, a nucleotide, a portion of cetirizine, chlorpheniramine, cholecalciferal, cilostaZol. genetic material, a nucleic acid, or a mixture thereof. Other cimetidine, cinnarizine, ciprofloxacin, cisapride, clarithro examples of Suitable hydrophilic active ingredients include: mycin, clemastine, clomiphene, clomipramine, clopidogrel, 60 acarbose; acyclovir, acetyl cysteine; acetylcholine chloride; codeine, coenzyme Q10, cyclobenzaprine, cyclosporin, alatrofloxacin; alendronate; aglucerase; amantadine hydro danazol, dantrolene, dexchlorpheniramine, diclofenac, chloride; ambenomium; amifostine; amiloride hydrochlo dicoumarol, digoxin, dehydroepiandrosterone, dihydroer ride; aminocaproic acid; amphotericin B; antihemophilic fac gotamine, dihydrotachysterol, dirithromycin, doneZepil, tor (human), antihemophilic factor (porcine); antihemophilic efavirenz, eposartan, ergocalciferol, ergotamine, essential 65 factor (recombinant), aprotinin; asparaginase; atenolol; atra fatty acid sources, etodolac, etoposide, famotidine, fenofi curium besylate; atropine; azithromycin; aztreonam, BCG brate, fentanyl, fexofenadine, finasteride, fluconazole, flurbi vaccine; bacitracin; becallennin; belladona; bepridil hydro US 8,840,924 B2 25 26 chloride; bleomnycin Sulfate; calcitonin human; calcitonin active agents (e.g. pharmaceutical agents) which may be used salmon; carboplatin: capecitabine; capreomycin Sulfate; in the compositions of the present invention include both cefamandole nafate; cefazolin Sodium, cefepime hydrochlo water soluble and water insoluble drugs. Examples of such ride, cefixime; cefonicid sodium, cefoperaZone; cefotetan therapeutically active agents include antihistamines (e.g., di disodium, cefotaxime; cefoxitin Sodium, ceftizoxime; ceftri menhydrinate, diphenhydramine, chlorpheniramine and dex axone, cefuroxime axetil, cephalexin; cephapirin Sodium; chlorpheniramine maleate), analgesics (e.g., aspirin, codeine, cholera vaccine; chorionic gonadotropin; cidofovir, cisplatin: morphine, dihydromorphone, oxycodone, etc.), non-steroi cladribine; clidinium bromide; clindamycin and clindamycin dal anti-inflammatory agents (e.g., naproxyn, diclofenac, derivatives; ciprofloxacin; clodronate; colistimethate indomethacin, ibuprofen, Sulindac), anti-emetics (e.g., meto Sodium; colistin Sulfate; corticotropin; cosyntropin; cro 10 clopramide), anti-epileptics (e.g., phenytoin, meprobamate molyn Sodium; cytarabine; dalteparin Sodium; danaparoid; and nitrezepam), vasodilators (e.g., nifedipine, papaverine, desferrioxamine; denileukin diflitox; desmopressin; diatri diltiazem and nicardirine), anti-tussive agents and expecto Zoate meglumine and diatrizoate sodium; dicyclomine; rants (e.g., codeine phosphate), anti-asthmatics (e.g. theo didanosine; dirithromycin; dopamine hydrochloride; dornase phylline), antacids, anti-spasmodics (e.g., atropine, Scopola alpha: doxacurium chloride: doxorubicin; etidronate diso 15 mine), antidiabetics (e.g., insulin), diuretics (e.g., ethacrynic dium; enalaprilat, enkephalin; enoxaparin; enoxaprin acid, bendrofluazide), anti-thypotensives (e.g., propranolol. Sodium; ephedrine; epinephrine; epoetin alpha; erythromy clonidine), antihypertensives (e.g., clonidine, methyldopa), cin; esmolol hydrochloride; factor IX; famciclovir; fludara bronchodilators (e.g., albuterol), Steroids (e.g., hydrocorti bine; fluoxetine; foScamet Sodium; ganciclovir, granulocyte Sone, triamcinolone, prednisone), antibiotics (e.g., tetracy colony stimulating factor, granulocyte-macrophage stimulat cline), antihemorrhoidals, hypnotics, psycho-tropics, antidi ing factor; growth hormones—recombinant human; growth arrheals, mucolytics, sedatives, decongestants, laxatives, hormone—bovine; gentamycin; glucagon; glycopyrolate; Vitamins, stimulants (including appetite Suppressants such as gonadotropin releasing hormone and synthetic analogs phenylpropanolamine), as well as salts, hydrates, and sol thereof, GnRH; gonadorelin; grepafloxacin; haemophilus B vates of the same. The above list is not meant to be exclusive. conjugate vaccine; Hepatitis A virus vaccine inactivated; 25 In certain embodiments, the therapeutically active agent Hepatitis B virus vaccine inactivated; heparin Sodium; indi include hydromorphone, oxycodone, dihydrocodeine, navir Sulfate; influenza virus vaccine; interleukin-2; interleu codeine, dihydromorphine, morphine, buprenorphine, salts, kin-3; insulin-human, insulin lispro; insulin procine; insulin hydrates and Solvates of any of the foregoing, mixtures of any NPH; insulin aspart; insulin glargine; insulin detemir, inter of the foregoing, and the like. In other embodiments, the feron alpha; interferon beta; ipratropium bromide; ifosfa 30 active agent is a locally active therapeutic agent and the mide; Japanese encephalitis virus Vaccine; lamivudine; leu environment of use may be, e.g., the gastrointestinal tract, or covorin calcium; leuprolide acetate, levofloxacin; lincomycin body cavities such as the oral cavity, periodontal pockets, and lincomycin derivatives; lobucavir, lomefloxacin; loracar Surgical wounds, the rectum or vagina. The liquid formula bef mannitol, is measles virus vaccine; meningococcal vac tions of the present invention may be provided orally, topi cine; menotropins; mepenZolate bromide; mesalamine; 35 cally, Subcutaneously, intramuscularly, intraperitoneally, methenamine; methotrexate; methScopolamine; metfonnin intraocularly, intraossealy, nasally, urethrally, mucosally, hydrochloride; metoprolol; mezocillin Sodium; mivacurium vaginally, rectally, intradurally, epidurally and the like. The chloride; mumps viral vaccine; nedocromil Sodium; neostig liquid formulation of the present invention may also be pro mine bromide; neostigmine methyl Sulfate; neurontin; nor vided as a mist, e.g., to the deep lung (alveolarly). floxacin; octreotide acetate; ofloxacin; olpadronate; oxyto 40 Locally active pharmaceutical agents of use with the cin, pamidronate disodium; pancuronium bromide; present inveention include antifungal agents (e.g., amphoteri paroxetine; perfloxacin; pentamidine isethionate; pentosta cin B, clotrimazole, nystatin, ketoconazole, miconazol, etc.), tin, pentoxifylline; periciclovir, pentagastrin; pentholamine antibiotic agents (penicillins, cephalosporins, erythromycin, mesylate; phenylalanine; physostigmine Salicylate; plague tetracycline, aminoglycosides, etc.), antiviral agents (e.g., vaccine; piperacillin Sodium; platelet derived growth factor 45 acyclovir, idoxuridine, etc.), breath fresheners (e.g. chloro human; pneumococcal vaccine polyvalent; poliovirus vac phyll), antitussive agents (e.g., dextromethorphanhydrochlo cine inactivated; poliovirus vaccine live (OPV); polymyxin B ride), anti-cariogenic compounds (e.g. metallic salts of fluo Sulfate; pralidoxime chloride; pramlintide, pregabalin; pro ride, Sodium monofluorophosphate, Stannous fluoride, amine pafenone; propenthaline bromide; pyridostigmine bromide; fluorides), analgesic agents (e.g., methylsalicylate, salicylic rabies vaccine; residronate; ribavarin: rimantadine hydro 50 acid, etc.), local anesthetics (e.g., benzocaine), oral anti-Sep chloride; rotavirus Vaccine; salmeterol Xinafoate: Sinealide; tics (e.g., chlorhexidine and salts thereof, hexylresorcinol, Smallpox vaccine; solatol; somatostatin; Sparfloxacin; spec dequalinium chloride, cetylpyridinium chloride), anti-flam tinomycin; stavudine; streptokinase; streptozocin, suxam matory agents (e.g., dexamethasone, betamethasone, pred ethonium chloride; tacrine hydrochloride; terbutaline sulfate: nisone, prednisolone, triamcinolone, hydrocortisone, etc.), thiopeta, ticarcillin; tiludronate; timolol, tissue type plasmi 55 hormonal agents (oestriol), antiplaque agents (e.g., chlorhexi nogen activator; TNFR:Fc: TNK-tpA: trandolapril; trimetr dine and salts thereof, octenidine, and mixtures of thymol. exate gluconate; trospectinomycin; trovafloxacin; tub menthol, methysalicylate, eucalyptol), acidity reducing ocurarine chloride; tumor necrosis factor, typhoid vaccine agents (e.g., buffering agents such as potassium phosphate live; urea; urokinase; Vancomycin; Valacyclovir, Valsartan; dibasic, calcium carbonate, sodium bicarbonate, sodium and Varicella virus vaccine live; vasopressin and vasopressin 60 potassium hydroxide, etc.), and tooth desensitizers (e.g., derivatives; vecuronium bromide; vinblastine; Vincristine; potassium nitrate). This list is not meant to be exclusive. vinorelbine; vitamin B12: warfarin sodium; yellow fever vac The examples herein include pharmaceutically active com cine; Zalcitabine; Zanamivir, Zolendronate; zidovudine; phar pounds useful in the practice of the present invention, e.g., maceutically acceptable salts, isomers and derivatives antihistamines, decongestants, antitussives and/or expecto thereof, and mixtures thereof. 65 rants. Other actives for use with the present invention include, A wide variety of therapeutically active agents can be used but are not limited to: non-steroidal anti-inflammatory drugs in conjunction with the present invention. The therapeutically (NSAIDs) and other analgesic drugs such as acetominophen US 8,840,924 B2 27 28 and phenacetin. These materials are incorporated into the Phenylephrine hydrochloride is available in the form of the immediate or controlled release formulations of the invention levorotatory isomer, a white, odorless, non-hygroscopic, in amounts governed by the desired release characteristics of crystalline compound possessing a bitter taste. Phenylephrine the material in Such excipient base and Such that conventional hydrochloride has a melting point of 140-145 degrees C. and dosages comply with applicable federal Food and Drug is freely soluble in water and alcohol. Decongestant com Administration (FDA) or other regulations. pounds in the form of their free bases as well as their salts, Decongestants useful with the present invention (along e.g., hydrochloride, citrate, maleate, tannate, etc., are well with a salt form) are phenylephrine (bitartrate, tannate, HBr, known. HCl), phenylpropanolamine (HCl) and pseudoephedrine Dextromethorphan may be present in amounts of between (HCl). Furthermore, a number of herbal and/or natural decon 10 gestants are known in the art, all of which may be used with about 5 and about 20 milligrams per liquid dose, with a the present invention. general range of about 10 to about 15 milligrams. Bromphe Expectorants for use with the present invention include, niramine may be present in amounts of between about 0.5 and e.g., guaifenesin, terpin hydrate, (glyceryl guaiacolate), about 4.0 milligrams per liquid dose with a general range of potassium (iodide, citrate) and potassium guaicolsulfonate. 15 about 2.0 milligrams per liquid dose. Half or less of that Other expectorants, whether individual ingredients or com amount may be used in a pediatric form of the formulation. binations of ingredients may be used with the present inven The present invention may also include chlorpheniramine, tion. Furthermore, a number of herbal and/or natural expec which is an antihistamine used to relieve, e.g., allergic rhinitis torants are known in the art, all of which may be used with the (seasonal allergy). The symptoms of allergic rhinitis include: present invention. Sneezing, runny nose, itching, and watery eyes. Chlorphe Examples of antihistamines for use with the present inven niramine may also be used to treat immediate allergic reac tion (e.g., in Salt form) are chlorpheniramine (maleate), bro tions. Chlorpheniramine may be provided alone and in com mpheniramine (maleate), dexchlorpheniramine (maleate), bination with other prescription or nonprescription drugs, dexbrompheniramine (maleate), triprolidine (HCl), diphen e.g., to treat symptoms of allergy, colds, and upper respiratory hydramine (HCl), doxylamine (Succinate), tripelennamine 25 infections. (HCl), cyproheptatine (HCl), bromodiphenhydramine (HCl). The pharmaceutical composition and/or the Solid carrier phenindamine (tartrate), pyrilamine (maleate, tannate) and particles can be coated with one or more enteric coatings, seal aZatadine (maleate). Antitussives that may be used with the coatings, film coatings, barrier coatings, compress coatings, present invention (with salt form) include: caramiphen (edi fast disintegrating coatings, or enzyme degradable coatings. sylate), dextromethorphan (HBO and codeine (phosphate, 30 Multiple coatings may be applied for desired performance. sulfate). A number of herbal and/or natural antihistamines are Further, some actives may be provided for slow release, pull known in the art, all of which may be used with the present satile release, controlled release, extended release, delayed invention. release, targeted release, synchronized release, or targeted Other actives may also be included with the present inven delayed release. For release/absorption control, solid carriers tion, e.g., non-steroidal anti-inflammatory drugs (NSAIDs) 35 can be made of various component types and levels or thick Such as propionic acid derivatives; acetic acid derivatives; nesses of coats, with or without an active ingredient. Such fenamic acid derivatives; biphenylcarboxylic acid deriva diverse solid carriers can be blended in a dosage form to tives; and oxicams. Examples of propionic acid derivatives achieve a desired performance. The compositions may be include: ibuprofen, naproxen, ketoprofen, flurbiprofen, feno formulated for oral, nasal, buccal, ocular, urethral, transmu profen, Suprofen, fenbufen, and fluprofen may be mentioned 40 cosal, vaginal, topical or rectal delivery, although oral deliv as preferred compounds. Acetic acid derivatives derivatives ery is used mostly. include: tolmetin Sodium, Zomepirac, Sulindac and The present invention may also contain a plasticizer and indomethacin. Fenamic acid derivatives derivatives include: possibly other coating excipients such as colorants, talc, and/ mefenamic acid and meclofenamate sodium. Diflunisal and or magnesium Stearate, which are well known in the art. flufenisal are biphenylcarboxylic acid derivatives, while oxi 45 Suitable plasticizers include: triethylcitrate (citroflex 2), tri cams include piroXicam, Sudoxicam and isoxicam. Other acetin (glyceryl triacetate), acetyl triethyl citrate, carbowax analgesics for use with the present invention include acetomi 400 (polyethylene glycol 400), diethyl phthalate, tributyl cit nophen and phenacetin. Naproxen may be present in amounts rate, acetylated monoglycerides, glycerol, fatty acid esters, of about 50 to about 250 milligrams per dose, however, propylene glycol, and dibutyl phthalate. In particular, anionic naproxen may be used in amounts of between about 100 and 50 carboxylic acrylic polymers usually will contain about 5-25% about 150 milligrams per liquid dose. by weight of a plasticizer, especially dibutyl phthalate, poly Phenylephrine may be present in amounts of between ethylene glycol, triethyl citrate and triacetin. Conventional about 15 and about 60 milligrams per liquid dose. Phenyle coating techniques such as spray or pan coating are employed phrine is generally in amounts of about 5 to about 30 milli to apply coatings. The coating thickness must be sufficient to grams per liquid dose, with half or less of that amount used in 55 ensure that the oral dosage form remains intact until the a pediatric form of the formulation. In one example of the desired site of topical delivery in the lower intestinal tract is present invention, phenylephrine is provided in the amount of reached. about 15 mg for extended release. Phenylephrine hydrochlo It should be appreciated that there is considerable overlap ride is an orally effective nasal decongestant. Chemically it is between the above-listed additives in common usage, since a (S)-3-hydroxy-CI(methylamino)methylbenzenemethanol 60 given additive is often classified differently by different prac hydrochloride. Phenylepherine is a synthetic, optically active titioners in the field, or is commonly used for any of several sympathomimetic amine that has one hydroxyl group on the different functions. Thus, the above-listed additives should be benzene ring. The hydroxyl group is placed in the position taken as merely exemplary, and not limiting, of the types of meta to the aliphatic side chain. The meta position affords additives that can be included in compositions of the present optimal activity and phenylepherine (neo-synephrine) 65 invention. The amounts of such additives may be readily replaced an older preparation, Synephrine, in which the determined by one skilled in the art, according to the particu hydroxyl was in the para position. lar properties desired. US 8,840,924 B2 29 30 Additives may be include, e.g., pre-mixed propylene gly wherein the coated drug-ion-exchange resin complex is col, glycerin, citric acid, sodium benzoate, povidone (kolli coated with a controlled release coating, don 30), sorbitol solution and the like. Flavorants, sweeten and wherein the directly compressible, free-flowing phar ers, preservatives, bitter masking agent, thickeners and the maceutical excipient aids in the liberation of the coated like may also be added to the blender. In one example, the 5 drug-resin complex in the mouth through disintegration. flavorants may be lemon, bubblegum, grape, wild cherry or 2. The composition of claim 1, wherein the drug in the other flavors, with Sweeteners including saccharin or honey. drug-ion-exchange resin complex comprises dextromethor In addition, a glycerin Solution may be added in addition to phan, codeine, morphine, hydrocodone, hyoscyamine, mogu water, e.g., double deionized water. isteine, pseudoephedrine, chlorpheniramine, phenylprop In addition the present invention may be in the form of a 10 chewing gum formulation based on natural rubber have been anolamine, pharmaceutically acceptable salts of the same or widely used in the pharmaceutical industry. The advantages combinations thereof. are the pleasant and popular dosage form and rapid, Sublin 3. The composition of claim 1, further comprising one or gual absorption of an active ingredient. When in the form of more flavorants, Sweeteners, coolants, dyes, or combinations and mixtures thereof. a chewing gum the present invention may include waxes. Such 15 as, for example, beeswax, Solid paraffin, oZocerite, polyols, 4. The composition of claim 1, further comprising one or cellulose esters, pharmaceutically active materials, flavoring more excipients, one or more binders or combinations and agents, Sweeteners, colorants, Stearic acid, calcium Stearate, mixtures thereof. magnesium Stearate, solubilizers, chelating agents, Surface 5. The composition of claim 1, wherein the coated drug stabilizer, additives, or similar Substances, may be used to ion-exchange resin complex comprises polistirex, polacrilex ensure a longer chewing time, have proven particularly or combinations thereof. advantageous with regard to the chewability. 6. The composition of claim 1, wherein the composition In yet another embodiment, the formulation may be a com comprises pseudoephedrine polistirex and chlorpheniramine bination of a soft-gel or liquid interior coated with a more firm polacrilex. exterior. For example, certain agents may be provided for 25 7. The composition of claim 1, wherein the resin in the immediate release in a thixotropic gel in the interior of a gel coated drug-ion-exchange resin complex comprises one or or chewing-gum-like exterior. more cationic exchange resins. It will be understood that particular embodiments 8. The composition of claim 1, wherein the coated drug described herein are shown by way of illustration and not as ion-exchange resin complex comprises a divinylbenzene Sul limitations of the invention. The principal features of this 30 fonic acid cationic exchange resin. invention can be employed in various embodiments without departing from the scope of the invention. Those skilled in the 9. The composition of claim 1, wherein the composition art will recognize, or be able to ascertain using no more than comprises a hardness of between about 5 and about 15 kPa. routine experimentation, numerous equivalents to the specific 10. The composition of claim 1, wherein the composition procedures described herein. Such equivalents are considered 35 has at least about 20 percent better mouth-feel. to be within the scope of this invention and are covered by the 11. The composition of claim 1, wherein the coated drug claims. ion-exchange resin complex controlled release coating com All publications and patent applications mentioned in the prises a diffusion barrier coating. specification are indicative of the level of skill of those skilled 12. The composition of claim 11, wherein the diffusion in the art to which this invention pertains. All publications and 40 barrier coating is a time release coating. patent applications are herein incorporated by reference to the 13. A compressed, orally disintegrating, controlled release same extent as if each individual publication or patent appli taste-masked hyoscyamine pharmaceutical composition cation was specifically and individually indicated to be incor according to claim 1 comprising: porated by reference. a coated hyoscyamine-ion-exchange resin complex; and All of the compositions and/or methods disclosed and 45 a directly compressible, free-flowing pharmaceutical claimed herein can be made and executed without undue excipient that aids in the liberation of the coated hyos experimentation in light of the present disclosure. While the cyamine-ion-exchange resin complex in the mouth compositions and methods of this invention have been through disintegration. described in terms of preferred embodiments, it will be appar 14. The composition of claim 13, further comprising one or ent to those of skill in the art that variations may be applied to 50 more flavorants, Sweeteners, coolants, dyes, or combinations the compositions and/or methods and in the steps or in the and mixtures thereof. sequence of steps of the method described herein without 15. The composition of claim 13, further comprising one or departing from the concept, spirit and scope of the invention. more excipients, one or more binders or combinations and More specifically, it will be apparent that certain agents which mixtures thereof. are both chemically and physiologically related may be Sub 55 16. The composition of claim 1, wherein the directly com stituted for the agents described herein while the same or pressible, free-flowing pharmaceutical excipient comprises a similar results would beachieved. All such similar substitutes water-soluble compressible carbohydrate. and modifications apparent to those skilled in the art are 17. The composition of claim 1, further comprising one or deemed to be within the spirit, scope and concept of the more amorphous Sugars. invention as defined by the appended claims. 60 18. The composition of claim 1, further comprising a plas What is claimed is: ticizer. 1. A compressed, orally disintegrating, controlled release 19. The composition of claim 1, wherein said controlled taste-masked pharmaceutical composition comprising: release coating comprises a delayed release coating. a coated drug-ion-exchange resin complex and a directly 20. The composition of claim 19, wherein the drug in said compressible, free-flowing pharmaceutical excipient, 65 drug-ion-exchange resin complex comprises an analgesic wherein the composition effectively masks an unpalatable drug, anti-inflammatory drug, central nervous system agent, taste associated with delivery of the drug, anti-hypertensive drug, or an anti-hyperactive drug. US 8,840,924 B2 31 32 21. The composition of claim 20, wherein the drug in said drug-ion-exchange resin complex comprises an anti-hyper active drug. 22. The composition of claim 19, wherein the drug in said drug-ion-exchange resin complex comprises amphetamine. 23. The composition of claim 1, wherein the drug in said drug-ion-exchange resin complex comprises an analgesic drug, anti-inflammatory drug, central nervous system agent, anti-hypertensive drug, or an anti-hyperactive drug. 24. The composition of claim 23, wherein the drug in said 10 drug-ion-exchange resin complex comprises an anti-hyper active drug. 25. The composition of claim 1, wherein the drug in said drug-ion-exchange resin complex comprises amphetamine.

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