(12) United States Patent (10) Patent No.: US 8,603,440 B2 Andersen Et Al

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(12) United States Patent (10) Patent No.: US 8,603,440 B2 Andersen et al. (45) Date of Patent: Dec. 10, 2013

(54) COMPRESSED CHEWING GUM TABLET 5,378,131 A 1/1995 Greenberg 5,580,590 A 12/1996 Hartman (75) Inventors: Carsten Andersen, Vejle (DK); Gitte 5,679.3975,800,848 A 10,9, 19971998 YatkaKuroda et et al. al. Lorenzen, Vejle Øst (DK); Nicolai 5.866.179 A 2, 1999 Testa Arent, Horsens (DK); Bitten 6,013,287 A 1/2000 Bunczek et al. Thorengaard, Vejle Øst (DK); Helle 6,017,566 A 1/2000 Bunczek et al. Wittorff, Vejle Øst (DK) 6,194,008 B1 2/2001 Li et al. 6,235,318 B1 5/2001 Lombardy, Jr. et al. 6,436,899 B2 8, 2002 Portman (73) Assignee: Fertin Pharma A/S (DK) 6,468,962 B1 10/2002 Portman - 6,471,945 B2 10/2002 Luo et al. (*) Notice: Subject to any disclaimer, the term of this 6.479,071 B2 11/2002 Holme et al. patent is extended or adjusted under 35 (Continued) U.S.C. 154(b) by 274 days. FOREIGN PATENT DOCUMENTS (21) Appl. No.: 12/819,907 CA 252351.0 A1 11 2004 (22) Filed: Jun. 21, 2010 EP O711506 A2 5, 1996 (65) Prior Publication Data (Continued) US 2010/O255063 A1 Oct. 7, 2010 OTHER PUBLICATIONS FDA. Comparative Chenmical Analysis of Different Lots of Ariva, Related U.S. Application Data 2002, pp. 1-4, www.fda.gov/ohrms/DOCKETS/daily/02/Nov02/ (63) Continuation of application No. 111502/02p-0075-Sup0002-02-attach-a-vol2.pdf.M ck PCT/DK2007/000563, filed on Dec. 20, 2007. (Continued) (51) Int. Cl. Primary Examiner — Benjamin Packard A6 IK9/68 (2006.01) (74) Attorney, Agent, or Firm — St. Onge Steward Johnston A6 IK3I/44 (2006.01) & Reens LLC AOIN 43/40 (2006.01) (52) U.S. Cl. (57) ABSTRACT USPC ------grgrrr. 424/48: 514/343 A compressed chewing gum tablet includes one or more (58) Field of Classification Search pharmaceutically active ingredients and one or more enhanc USPC ...... 426/3; 424/48; 514/343 ers, wherein the chewing gum tablet includes at least one See application file for complete search history. chewing gum module including a chewing gum composition, and wherein the chewing gum composition includes chewing (56) References Cited gum granules containing gum base, and wherein the enhanc ers are at least partly contained within at least a part of the U.S. PATENT DOCUMENTS chewing gum granules. 5,227,154 A 7/1993 Reynolds 5,300,305 A 4/1994 Stapler et al. 20 Claims, 3 Drawing Sheets

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(56) References Cited 2006/005.1455 A1* 3/2006 Andersen et al...... 426/3 2006/O198873 A1* 9/2006 Chan et al...... 424/443 U.S. PATENT DOCUMENTS 2007.0043200 A1 2/2007 Yamamoto et al. 6,485,739 B2 11, 2002 Luo et al. FOREIGN PATENT DOCUMENTS 6,558,690 B2 5/2003 Portman 6,613,363 B1 9, 2003 Li EP 1474993 A1 11, 2004 6,685,916 B1 2, 2004 Holme et al. EP 1554935 A1 7/2005 6,696,044 B2 2, 2004 Luo et al. EP 1693O86 A1 8, 2006 6,716,815 B2 4, 2004 Portman EP 1545234 B1 T 2008 6,733,818 B2 5, 2004 Luo et al. WO OO25598 A1 5, 2000 6,773,730 B1 8, 2004 Liu et al. WO 02102357 A1 12/2002 6,838,431 B2 1/2005 Portman WO 2004.004480 A1 1, 2004 6,846,500 B1 1/2005 Luo et al. WO 2004O2827O A1 4/2004 6,858.238 B2 2, 2005 Lee et al. WO 200403.2644 A2 4/2004 2001, 0021694 A1 9, 2001 Portman WO 2004O98305 A1 11 2004 2001/0043907 A1 11, 2001 Luo et al. WO 2006OOO232 A1 1, 2006 2002fOO71858 A1 6, 2002 Luo et al. WO 2006002622 A1 1, 2006 2002fOO98157 A1 T/2002 Holme et al. WO 2006O79.343 A1 8, 2006 2002/011058O A1 8, 2002 Portman WO 2006127618 A2 11/2006 2002/01 1991.5 A1 8, 2002 Portman 2002fO159955 A1 10, 2002 Luo et al. OTHER PUBLICATIONS 2003, OOO8810 A1 1, 2003 Portman 2003/OO99741 A1 5/2003 Gubler Food and Drug Administration, CFR, Title 21, Section 172,615, the 2003/O124064 A1 T/2003 Luo et al. Masticatory Substances, Synthetic; Apr. 1, 2005 edition; 2 pages. 2003. O157213 A1 8, 2003 Jenkins International Preliminary Report on Patentability and Written Opin 2003/0206993 A1 11, 2003 Gubler 2003/0215417 A1 11, 2003 Uchiyama et al. ion of the International Searching Authority; PCT/DK2007/000563: 2004/0001903 A1 1, 2004 Lee et al. Jun. 22, 2010; 6 pages. ck 2004/OO 13767 A1 1, 2004 Norman et al...... 426, 5 International Search Report; PCT/DK2007/000563; Sep. 24, 2008: 3 2004/OO81713 A1 4, 2004 Maxwell et al. pageS. 2004/O115305 A1 6, 2004 Andersen et al. H.P. Fiedler, Lexikon der Hilfstoffe für Pharmacie, Kosmetik und 2004/O136928 A1 T/2004 Holme et al. Angrenzende Gebiete, pp. 63-64 (1981). 2005/OOO8732 A1 1/2005 Gebreselassie et al. 2005/0O25721 A1 2, 2005 Holme et al. * cited by examiner U.S. Patent Dec. 10, 2013 Sheet 1 of 3 US 8,603.440 B2

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Fig. 7a Fig. 7b US 8,603,440 B2 1. 2 COMPRESSED CHEWING GUMITABLET In an embodiment of the invention, said compressed chew ing gum tablet comprises at least two individual coherent CROSS-REFERENCE TO RELATED compressed modules. APPLICATIONS In an embodiment of the invention, said compressed chew ing gum tablet comprises at least three individual coherent The present application is a continuation of pending Inter compressed modules. national patent application PCT/DK2007/000563 filed on In an embodiment of the invention, the compressed chew Dec. 20, 2007 which designates the United States and the ing gum tablet comprises one or more gum base free modules. content of which is incorporated herein by reference. In an advantageous embodiment of the invention, there are 10 applied gum base granules and bulk Sweetener particles hav FIELD OF THE INVENTION ing comparable particle sizes. According to embodiments of the invention, powder seg The present invention relates to the field of compressed regation is reduced and a more even distribution of pharma chewing gum. In particular, the present invention provides a ceutically active ingredients in the chewing gum composition compressed chewing gum tablet comprising pharmaceuti- 15 is obtained by applying gum base granules and bulk Sweet cally active ingredients and an enhancer. ener particles having comparable particle sizes. Small par ticles of the pharmaceutically active ingredients are advanta BACKGROUND OF THE INVENTION geously adhered to the larger particles by way of flavoring material or by way of a dry-binder. A problem related to compressed chewing gum is that for 20 In an embodiment of the invention, the compressed chew pharmaceutically active ingredients, which has to be accom ing gum tablet comprises two or more chewing gum modules. panied by an enhancer in order for a desirable uptake of the In an embodiment of the invention, the compressed chew pharmaceutically active ingredient, it is difficult to obtain a ing gum tablet comprises 2, 3, 4, or 5 modules. desired and satisfying release for both the pharmaceutically In an embodiment of the invention, the modules are layers. active ingredients and the enhancer. The problem is found in 25 In an embodiment of the invention, at least one of the particular when dealing with compressed chewing gums as pharmaceutically active ingredients is separated from at least compared to conventionally mixed chewing gum, as com one of the enhancers by location in different modules. pressed chewing gum tends to release active ingredients and When incorporating a pharmaceutically active ingredients enhancer relatively fast. and an enhancer which may affect each other negatively if Hereby the user of the compressed chewing gum will typi- 30 located in the same chewing gum composition, an advanta cally not achieve the optimal effect of neither the pharmaceu geous embodiment of the invention may be obtained by locat tically active ingredient nor the enhancer, as the release of ing the pharmaceutically active ingredient in one module and different active ingredients and enhancers are not possible to the enhancer in another module. By e.g. locating pharmaceu synchronize satisfyingly. tically active ingredient and enhancer in different layers, sta It is therefore an object of the present invention to provide 35 bility problems during Storage may be avoided. improved possibilities of designing a release profile of both A particularly advantageous embodiment of the invention pharmaceutically active ingredients and enhancers according has been obtained with nicotine located in one layer and a pH to a present desire. control agent, such as sodium carbonate, located in another layer. SUMMARY OF THE INVENTION 40 In an embodiment of the invention, two different pharma ceutically active ingredients are located in two different mod The invention relates to compressed chewing gum tablet ules. comprising one or more pharmaceutically active ingredients Advantageously, different pharmaceutically active ingre and one or more enhancers, wherein the chewing gum tablet dients which may affect each other negatively if located in the comprises at least one chewing gum module comprising a 45 same chewing gum composition, or which are intended to be chewing gum composition, and wherein the chewing gum released from the chewing gum differently, may be located in composition comprises chewing gum granules containing different modules, such as layers, of the chewing gum tablet. gum base, and wherein said enhancers are at least partly In an embodiment of the invention, at least one pharma contained within at least apart of said chewing gum granules. ceutically active ingredient and at least one enhancer are By the present invention there is provided a chewing gum 50 located in the same module. in the form of a compressed tablet, which facilitates both a In an embodiment of the invention, at least a part of the careful incorporation of pharmaceutically active ingredient pharmaceutically ingredients are incorporated in at least a and a controlled delivery of the pharmaceutically active part of the chewing gum granules. ingredient and an associated enhancerto a person when chew In an embodiment of the invention, at least a part of the ing the tablet. A particular advantage has been obtained when 55 pharmaceutically active ingredients are adhered to bulk incorporating at least a part of the enhancer in the chewing sweetener particles by way of flavor. gum granules. Hereby, at least a part of the enhancer is In an embodiment of the invention, at least a part of the release-administered by the chewing gum granules, and a pharmaceutically active ingredients are adhered to chewing release of enhancer matching the release of the pharmaceuti gum granules by way of flavor. cally active ingredient has been obtained. 60 By the phrase “adhered to it is implied that the association According to advantageous embodiments of the invention, of two kinds of particles, e.g. pharmaceutically active ingre there has been provided compressed chewing gum tablets dient particles and chewing gum granules or bulk Sweetener facilitating a concerted release of pharmaceutically active in Some cases is mediated by a third kind of particle, e.g. ingredients and one or more enhancers. By incorporating at flavor particles. least a part of the enhancers in the chewing gum granules, the 65 In an embodiment of the invention, at least a part of the release of enhancer has been prolonged thereby optimizing pharmaceutically active ingredients are adhered to dry-binder the uptake of pharmaceutically active ingredients. particles. US 8,603,440 B2 3 4 The pharmaceutically active ingredients have average par that pH as measured during chewing in a mastication device ticle sizes which are relatively small, such as below 100 um. is kept above the highest pKa value of the pharmaceutically It has been found advantageous to bind the pharmaceutically active ingredient for at least a part of a chewing period. active ingredients to a dry-binder and/or to the Surrounding In an embodiment of the invention, said chewing gum chewing gum granules and/or bulk Sweetener particles. The granules consist of gum base. free flowability of the pharmaceutically active ingredients in In an embodiment of the invention, the enhancer is a pH the chewing gum composition has thereby been reduced and control agent. thereby the tendency to segregation has been reduced. A In an embodiment of the invention, at least a part of the pH relatively even distribution of pharmaceutically active ingre control agent is incorporated in the chewing gum granules dients in the chewing gum composition has been the result. 10 and at least a part of the pH control agent is part of the In an embodiment of the invention, the dry binders are chewing gum composition as a powder. selected from the group consisting of mikro-crystalline cel According to a preferred embodiment of the invention, lulose (MCC), silicified micro-crystalline cellulose (SMCC), incorporation of pH control agent in the chewing gum gran spray dried lactose, fast flow lactose, anhydrous lactose, ules and addition of pH control agent as a powder in the Sucrose, mannitol, mannitol EZ. dextrose, fructose, Sorbitol, 15 chewing gum composition facilitates a biphasic release of pH poVidone, copovidone, dicalcium phosphate (DCP), starch control agent during chewing of the chewing gum tablet. (corn, potato and rice), pre-gelatinized starch, or any combi In an embodiment of the invention, said pharmaceutically nation thereof. active ingredients are at least partly contained within at least In an embodiment of the invention, at least a part of the a part of said chewing gum granules. pharmaceutically active ingredients are interspersed between In an embodiment of the invention, one or more modules said chewing gum granules. comprise chewing gum granules having average particle sizes In an embodiment of the invention, at least a part of said above about 800 um and one or more modules comprise enhancers are interspersed between said chewing gum gran chewing gum granules having average particle sizes below ules. about 800 um. According to advantageous embodiments of the invention, 25 In an embodiment of the invention, at least 50% of said a part of the enhancers are interspersed between the chewing chewing gum granules have an average diameter below 1600 gum granules thereby obtaining a faster release of these lm. enhancers. Having a part of the enhancers within the chewing In an embodiment of the invention, at least 50% of said gum granules and a part of the enhancers outside the chewing chewing gum granules have an average diameter above 100 gum granules, an advantageous biphasic release may be 30 lm. obtained, whereby the release of enhancer may be adjusted to In an embodiment of the invention, said chewing gum provide a concerted release of pharmaceutically active ingre granules substantially consists of gum base. dients and one or more enhancers. When a chewing gum granule as mentioned herein Sub In an embodiment of the invention, at least a part of said stantially consists of gum base, the result is gum base gran enhancers are incorporated in said chewing gum granules. 35 ules typically based mainly on natural and/or synthetic resins In an embodiment of the invention, upon mastication of and/or elastomers. Such gum base granules may find appli said chewing gum tablet in an oral cavity, dissolution of said cation in combination with a variety of flavoring, Sweetening pH control agent and said pharmaceutically active ingredient and so on. begin, such that said oral cavity has a salivary pH that is above In an embodiment of the invention, said chewing gum pK, of said pharmaceutically active ingredient. 40 granules comprise chewing gum ingredients. In an embodiment of the invention, upon mastication of In an embodiment of the invention, said chewing gum said chewing gum tablet in an oral cavity, dissolution of said granules are agglomerates. pH control agent and said pharmaceutically active ingredient In embodiments of the invention, the chewing gum granule begin, such that said oral cavity has a salivary pH that is below may comprise chewing gum ingredients such as filler, color pKa of said pharmaceutically active ingredient. 45 ing agent, flavoring agent, high-intensity Sweetener, bulk In an embodiment of the invention, said chewing gum Sweetener, softener, emulsifier, acidulant, antioxidant, further composition comprises a basic pharmaceutically active conventional chewing gum ingredients and more. ingredient and a pH control agent, which facilitates that pH in In an embodiment of the invention, said compressed chew the oral cavity is kept above the highest pKa value of said ing gum tablet consist of one compressed module. basic pharmaceutically active ingredient for at least a part of 50 In an embodiment of the invention, the pharmaceutically a chewing period. active ingredients are selected from the group consisting of In an embodiment of the invention, said chewing gum antihistamines, anti-Smoking agents, agents used for diabe composition comprises an acidic pharmaceutically active tes, decongestrants, peptides, pain-relieving agents, antacids, ingredient and a pH control agent, which facilitates that pH in nausea-relieving agents, statines, or any combination thereof. the oral cavity, is kept below the lowest pKa value of said 55 In an embodiment of the invention, wherein the pharma acidic pharmaceutically active ingredient for at least a part of ceutically active ingredients are selected from the group con a chewing period. sisting of cetirizine, levo cetirizine, nicotine, nicotine polac In an embodiment of the invention, said pH control agent rilex, nicotine in combination with alkaline agents, raises the pH inside the mouth to be above the pKa of said metformine, metformine HCL, phenylephrine, GLP-1. pharmaceutically active ingredient within about 5 minutes of 60 exenatide, deca-peptide, KSL-W (acetat), fluor, chlorhexi chewing said composition. dine, or any combination thereof. In an embodiment of the invention, said pH control agent In an embodiment of the invention, the pharmaceutically adjusts the pH inside the mouth to be below the pKa of said active ingredients are selected from the group consisting of pharmaceutically active ingredient within about 5 minutes of loratadine, des-loratadine, nicotine bitartrate, nicotine in chewing said composition. 65 combination with caffeine, nicotine antagonists, combina In an embodiment of the invention, said chewing gum tions thereof or compounds comprising one or more of these, composition comprises a pH control agent, which facilitates pseudoephedrine, flurbiprofen, paracetamol, acetyl salicylic US 8,603,440 B2 5 6 acid, Ibuprofen, antacida, cimetidine, ranitidine, iV-ethyl-2-(1-ethyl-hydroxy-2-nitrosohydrazino)-etha ondansetron, granisetron, metoclopramid, simvastatin, lovas namine, SNAP S-nitroso-N-acetyl-DL-penicillamine, tatin, fluvastatin, acyclovir, benzydamin, rimonabant, Vareni NORI, NOR4, deacylmethylsulfoxide, azone, salicylamide, cline, sildenafil, naltrexone, fluor in combination with fruit glyceryl-I.3-diacetoacetate, I.2-isopropylideneglycerine-3- acids, derivatives, salts or isomers of chlorhexidine, or any acetoacetate), Amino acids, Amino acid salts, monoami combination thereof. nocarboxlic acids, Glycine, alanine, phenylalanine, proline, In an embodiment of the invention, said enhancers are hydroxyproline, hydroxyamino acids, serine, acidic amino selected from the group consisting of bile salts, cetomac acids, aspartic acid, Glutamic acid, Basic amino acids, rogols, chelating agents, citrates, cyclodextrins, detergents, Lysine, N-acetylamino acids, N-acetylalanine, N-acetylphe enamine derivatives, fatty acids, labrasol, lecithins, phospho 10 nylalanine, TM-acetylserine, N-acetylglycine, N-acetyl lipids, Syntetic and natural Surfactants, nonionic Surfactants, cell envelope disordering compounds, solvents, steroidal ysine, N-acetylglutamic acid, N-acetylproline, N-acetylhy detergents, chelators, solubilization agents, charge modify droxyproline, lactic acid, malic acid and citric acid and alkali ing agents, pH control agents, degradative enzyme inhibitors, metal salts thereof, pyrrolidonecarboxylic acids, alkylpyr mucolytic or mucus clearing agents, membrane penetration 15 rolidonecarboxylic acid esters, N-alkylpyrrolidones, proline enhancing agents, modulatory agents of epithelial junction acyl esters, sodium lauryl phosphate, Sodium lauryl Sulphate, physiology, vasodilator agents, selective transport-enhancing Sodium oleyl phosphate, Sodium myristyl Sulphate, polyoxy agents, or any combination thereof. pH control agents include ethylene alkyl ethers, polyoxyethylene alkyl esters, and cap buffers. roic acid, alkylsaccharide, fusidic acid, polyethylene glycol, In an embodiment of the invention, said enhancers are cetyl alcohol, polyvinylpyrolidone, Polyvinyl alcohol, Lano selected from the group consisting of cetylpyridinium chlo lin alcohol, Sorbitan monooleate, Ethylene glycol tetraacetic ride (CPC), benzalkonium chloride, sodium lauryl sulfate, acid, Bile acid conjugate with taurine, Cholanic acid and polysorbate 80, Polysorbate 20, cetyltrimethylammonium salts, Cyclodextran, Cyclodextrin, Cyclodextrin (beta), bromide, laureth9, sodium salicylate, sodium EDTA, EDTA, Hydroxypropyl-f-cyclodetran, Sulfobutylether-f-cyclodex aprotinin, Sodium taurocholate, Saponins, bile salt deriva 25 tran, Methyl-3-cyclodextrin, Chitosan glutamate, Chitosan tives, fatty acids. Sucrose esters, aZone emulsion, dextran acetate, Chitosan hydrochloride, Chitosan hydrolactate, 1-O- Sulphate, linoleic acid, labrafil, transcutol, urea, aZone, non alkyl-2-hydroxy-sn-glycero-3-phosphocholine, 3-O-alkyl-2- ionic surfactants, sulfoxides, sauric acid/PG, POE 23 lauryl acetoyl-sn-glycero-1-phosphocholine, 1-O-alkyl-2-O- ether, methoxysalicylate, dextran Sulfate, methanol, ethanol, acetyl-sn-glycero-3-phospho(N.N.N-trimethyl) Sodium cholate, Sodium taurocholate, Lysophosphatidyl 30 hexanolamine, Propylene glycol, Tetradecylmaltoside choline, Alkylglycosides, polysorbates, Sorbitan esters, (TDM). Sucrose dedecanoate. Poloxamer block copolymers, PEG-35 castor oil, PEG-40 In an embodiment of the invention, said pH control agents hydrogenated castor oil, Caprocaproyl macrogol-8 glycer are selected from the group consisting of Acetic acid, Adipic ides, PEG-8 caprylic/capric, glycerides, Dioctyl sulfosucci acid, Citric acid, Fumaric acid, Glucono-6-lactone, Gluconic nate, Polyethylene lauryl ether, Ethoxydiglycol, Propylene 35 acid, Lactic acid, Malic acid, Maleic acid, Tartaric acid, Suc glycol, mono-di-caprylate, Glycerol monocaprylate, Glyc cinic acid, Propionic acid, Ascorbic acid, Phosphoric acid, eryl fatty acids (C. sub.8-C. Sub. 18) ethoxylated. Sodium orthophosphate, Potassium orthophosphate, Cal Oleic acid, Linoleic acid, Glyceryl caprylate/caprate, cium orthophosphate, Sodium diphosphate, Potassium Glyceryl monooleate, Glyceryl monolaurate, Capryliccapric diphosphate, Calcium diphosphate, Pentasodium triphos triglycerides, Ethoxylated nonylphenols, PEG-(8-50) stear 40 phate, Pentapotassium triphosphate, Sodium polyphosphate, ates, Olive oil PEG-6, esters, Triolein PEG-6 esters, Lecithin, Potassium polyphosphate, Carbonic acid, Sodium carbonate, d-alpha tocopherol polyethylene glycol 1,000 succinate, Cit Sodium bicarbonate, Potassium carbonate, Calcium carbon ric acid, Sodium citrate, BRIJ, Sodium laurate, 5-methox ate, Magnesium carbonate, Magnesium oxide, or any combi ysalicylic acid, Bile salts, Acetyl salicylate. ZOT, Docosa nation thereof. hexaenoic acid, Alkylglycosides, Sodium glycocholate (GC 45 In an embodiment of the invention, said pharmaceutically Na), Sodium taurocholate (TC-Na), EDTA, Choline active ingredient in the compressed chewing gum tablet is in salicylate, Sodium caprate (Cap-Na), N-lauryl-beta-D-mal the form of a salt. topyranoside (LM), Diethyl maleate, Labrasol, Sodium sali In an embodiment of the invention, at least one of the cylate, Mentol, Alkali metal alkyl sulphate, Sodium lauryl pharmaceutically active ingredients is basic. Sulphate, Glycerin, Bile acid, Lecithin, phosphatidylcholine, 50 In an embodiment of the invention, at least one of the phosphatidylserine, sphingomyelin, phophatidylethanola pharmaceutically active ingredients is acidic. mine, cephalin, lysolecithin, Hyaluronic acid: alkalimetal In an embodiment of the invention, the compressed chew salts, sodium, alkaline earth and aluminum, Octylphenoxy ing gum tablet comprises the pharmaceutically active ingre polyethoxyethanol, Glycolic acid, Lactic acid, Chamomile dient in the form of metforminand the enhancers in the form extract, Cucumber extract, Borage oil. Evening primrose oil, 55 of sodium glycolate and/or sodium laurylsulfate. Polyglycerin, Lysine, Polylysine, Triolein, Monoolein, In an embodiment of the invention, the compressed chew Monooleates, Monolaurates, Polydocanol alkyl ethers, ing gum tablet comprises the pharmaceutically active ingre Chenodeoxycholate, Deoxycholate, Glycocholic acid, Tau dient in the form of cetirizine and the enhancers in the form of rocholic acid, Glycodeoxycholic acid, Taurodeoxycholic polysorbate 80. acid, Sodium glycocholate, Phosphatidylcholine, Phosphati 60 In an embodiment of the invention, the compressed chew dylserine, Sphingomyelin, Phosphatidylethanolamine, ing gum tablet comprises the pharmaceutically active ingre Cephalin, Lysolecithin, Alkali metal hyaluronates, Chitosan, dient in the form of exenatide and the enhancers in the form of Poly-L-arginine, Alkyl glucoside, Saccharide alkyl ester, L-O-phosphatidylcholine Didecanoyl (DDPC). Fusidic acid derivatives, Sodium taurdihydrofusidate In an embodiment of the invention, the compressed chew (STDHF), L-O-phosphatidylcholine Didecanoyl (DDPC), 65 ing gum tablet comprises the pharmaceutically active ingre Nitroglycerine, nitropruside, NCO5 3-(2-hydroxy-1-(me dient in the form of nicotine polacrilex and the enhancers in thyl-ethyl)-2-nitrosohydrazino)-1-propanamine, NOC 12 the form of sodium carbonate. US 8,603,440 B2 7 8 In an embodiment of the invention, said gum base com anemic preparations, C01 Cardiac therapy, C10 Serum lipid prises two or more ingredients selected from the group con reducing agents, D01 Antifungals for dermatological use, sisting of elastomers, elastomer plasticizers, resins, polyvinyl G03 Sex hormones, G04 Urologicals, MO1 Anti-inflamma acetate, hydrogenated resins, polyterpene, fillers, fats and tory and antirheumatic products, MO9 Other drugs for disor waxes, or any combination thereof. ders of the musculoskeletal system, NO1 Anesthetics, NO2 In an embodiment of the invention, said chewing gum analgesics, N07 Other nervous system drugs, R01 Nasal composition comprises one or more chewing gum ingredi preparations, R02 Throat preparations, R03 Drugs for entS. obstructive airway diseases, R05 Cough and cold prepara In an embodiment of the invention, said chewing gum tions, and R06 Antihistamines for systemic use, VO1 aller granules comprises said gum base and one or more chewing 10 gens, V04 diagnostic agents, or any combination thereof. gum ingredients. In an embodiment of the invention, said active ingredientis In an embodiment of the invention, said chewing gum selected from the therapeutical groups consisting of: ingredients are selected from the group consisting of bulk Antipyretic, Anti allergic, Anti-arrytmic. Appetite Suppres Sweeteners, flavors, dry-binders, tabletting aids, anti-caking sant, Anti-inflammatory, Broncho dilator, Cardiovascular agents, emulsifiers, antioxidants, enhancers, absorption 15 drugs, Coronary dilator, Cerebral dilator, Peripheral vasodi enhancers, pH control agents, high intensity Sweeteners, col lator, Anti-infective, Psychotropic, Anti-manic, Stimulant, ors, or any combination thereof. Decongestant, Gastro-intestinal sedative, Sexual dysfunction In an embodiment of the invention, the chewing gum gran agent, Desinfectants, Anti-anginal Substance, Vasodilator, ules comprise one or more chewing gum ingredients selected Anti-hypertensive agent, Vasoconstrictor, Migraine treating from the group consisting of bulk Sweeteners, flavors, dry agent, Anti-biotic, Tranquilizer, Anti-psychotic, Anti-tumor binders, tabletting aids, anti-caking agents, emulsifiers, anti drug, Anticoagulant, Hypnotic, Sedative, Anti-emetic, Anti oxidants, enhancers, absorption enhancers, pH control nauseant, Anti-convulsant, Neuromuscular agent, Hyper and agents, or any combination thereof. hypoglycaemic, Thyroid and anti-thyroid, Diuretic, Anti In an embodiment of the invention, one or more bulk sweet spasmodic, Uterine relaxant, Anorectics, Spasmolytics, Ana eners are provided as particles having average particle sizes 25 bolic agent, Erythropoietic agent, Anti-asthmatic, Expecto below 700 um, preferably below 500 um. rant, Cough suppressant, Mucolytic, Anti-uricemic agent, In an embodiment of the invention, the particles of bulk Dental vehicle, Breath freshener, Antacid, Anti-diuretic, sweetener have particle sizes in the range of 150 to 400 um. Anti-flatulent, Betablocker, Teeth Whitener, Enzyme, Co In an embodiment of the invention, the chewing gum gran enzyme, Protein, Energy Booster, Fiber, Probiotics, Prebiot ules in the chewing gum composition comprising pharmaceu 30 ics, Antimicrobial agent, NSAID, Anti-tussives, Decon tically active ingredients have average particle sizes below gestrants, Anti-histamines, Anti-diarrheals, Hydrogen 1500 um, preferably below 1000 um, more preferably below antagonists, Proton pump inhibitors, General nonselective 800 um, and most preferably below 600 um. CNS depressants, General nonselective CNS stimulants, In an embodiment of the invention, in the chewing gum Selectively CNS function modifying drugs, Antiparkin composition comprising pharmaceutically active ingredients, 35 Sonism, Narcotic-analgetics, Analgetic-antipyretics, Psy the average particle size of the chewing gum granules is at chopharmacological drugs, diagnostica sex hormones aller most 5 times larger, preferably at most 3 times larger, and gens, antifungal agents, Chronic Obstructive Pulmonary most preferably at most 2 times larger than the average par Disease (COPD) or any combination thereof. ticle size of the bulk sweetener particles. In an embodiment of the invention, said active ingredientis In an embodiment of the invention, the chewing gum gran 40 selected from the group consisting of ace-inhibitors, anti ules and the bulk Sweetener particles have average particle anginal drugs, antiarrhythrmas, anti-asthmatics, anti-choles sizes deviating at most 600%, preferably at most 400% from terolemics, analgesics, anesthetics, anticonvulsants, anti-de each other. pressants, anti-diabetic agents, anti-diarrhea preparations, In an embodiment of the invention, said active ingredientis antidotes, anti-histamines, anti-hypertensive drugs, anti-in selected from the group consisting of pharmaceuticals, nutra 45 flammatory agents, anti-lipid agents, antimanics, anti-nause ceuticals, medicaments, nutrients, nutritional Supplements, ants, anti-stroke agents, anti-thyroid preparations, anti-tumor drugs, dental care agents, herbals, and the like and combina drugs, anti-viral agents, acne drugs, alkaloids, amino acid tions thereof. preparations, anti-tussives, antiuricemic drugs, anti-viral In an embodiment of the invention, said active ingredientis drugs, anabolic preparations, systemic and non-systemic selected from the ATC anatomical groups consisting of agents 50 antiinfective agents, anti-neoplastics, anti-parkinsonian acting on: agents, anti-rheumatic agents, appetite stimulants, biological Aalimentary tract and metabolism, B blood and blood form response modifiers, blood modifiers, bone metabolism regu ing organs, C cardiovascular system, D dermatologicals, G lators, cardiovascular agents, central nervous system stimu genito urinary system and sex hormones, H Systemic hor lates, cholinesterase inhibitors, contraceptives, deconges monal preparations, Jantiinfectives for systemic use, Lanti 55 tants, dietary Supplements, dopamine receptor agonists, neoplastic and immunomodulating agents, M musculo-skel endometriosis management agents, enzymes, erectile dys etal system, N nervous system, P antiparasitic products, function therapies Such as sildenafil citrate, which is currently insecticides and repellents, R respiratory system and S sen marketed as ViagraTM, fertility agents, gastrointestinal agents, sory organs, V various, or any combination thereof. homeopathic remedies, hormones, hypercalcemia and In an embodiment of the invention, said active ingredientis 60 hypocalcemia management agents, immunomodulators, selected from the ATC therapeutical groups consisting of inmosuppressives, migraine preparations, motion sickness A01 Stomatological preparations, A02 Drugs for acid related treatments, muscle relaxants, obesity management agents, disorders, A04 Antiemetics and antinauseants, A06 Laxa osteoporosis preparations, oxytocics, parasympatholytics, tives, A07 Antidiarrheals, intestinal anti-inflammatory/anti parasympathomimetics, prostaglandins, psychotherapeutic infective agents, A08 Antiobesity preparations, excluding 65 agents, respiratory agents, sedatives, Smoking cessation aids diet products, A10 Drugs used in diabetes, A11 Vitamins, A12 Such as bromocryptine or nicotine, sympatholytics, tremor Mineral supplements, B01 Antithrombotic agents, B03 Anti preparations, urinary tract agents, vasodilators, laxatives, ant US 8,603,440 B2 10 acids, ion exchange resins, anti-pyretics, appetite Suppres In an embodiment of the invention, said center-fill is a solid sants, expectorants, anti-anxiety agents, anti-ulcer agents, or semi-liquid composition in combination with one or more anti-inflammatory Substances, coronary dilators, cerebral enzymes Suitable for enzymatic liquification of said Solid or dilators, peripheral vasodilators, psycho-tropics, stimulants, semi-liquid. anti-hypertensive drugs, vasoconstrictors, migraine treat In an embodiment of the invention, said center-fill com ments, antibiotics, tranquilizers, anti-psychotics, anti-tumor prises bulk Sweetener, high-intensity Sweetener, flavor or drugs, anti-coagulants, anti-thrombotic drugs, hypnotics, combinations thereof. anti-emetics, anti-nauseants, anti-convulsants, neuromuscu In an embodiment of the invention, said compressed chew lar drugs, hyper- and hypo-glycemic agents, thyroid and anti ing gum tablet comprises one or more encapsulation delivery thyroid preparations, diuretics, anti-spasmodics, terine relax 10 systems. In an embodiment of the invention, said one or more encap ants, anti-obesity drugs, erythropoietic drugs, anti Sulation delivery systems comprise at least one encapsulating asthmatics, cough Suppressants, mucolytics, DNA and material and at least one ingredient encapsulated within said genetic modifying drugs, and combinations thereof. encapsulating material. In an embodiment of the invention, said active ingredientis 15 In an embodiment of the invention, at least one of said selected from the group consisting of anti-histamines, decon encapsulation material comprises PVA. gestants, Smoking cessation aids, diabetes II agents, or any In an embodiment of the invention, at least one of said combination thereof. encapsulation material is selected from the group consisting In an embodiment of the invention, said active ingredientis of natural resin, such as a polyterpene resin; hydrogenated selected from the group consisting of metformin, cetirizine, Vegetable oil; wax; and combinations thereof. levo cetirizine, phenylephrine, flurbiprofen, nicotine, nico In an embodiment of the invention, at least one of said tine bitartrate, nicotine polacrilex, nicotine in combination encapsulation material comprises natural resin and PVA. with alkaline agents, nicotine in combination with caffeine, In an embodiment of the invention, at least one of said sodium picosulfate, fluor, fluor in combination with fruit encapsulation material comprises an active ingredient. acids, chlorhexidine, or any derivatives thereof, salts thereof, 25 In an embodiment of the invention, said chewing gum isomers thereof, nicotine antagonists, combinations thereof granules comprises biodegradable gum base. or compounds comprising one or more of these. In an embodiment of the invention, said biodegradable In an embodiment of the invention, said active ingredientis gum base comprises at least one biodegradable polyester selected from the group consisting of ephedrine, pseudo polymer. 30 In an embodiment of the invention, said biodegradable ephedrine, caffeine, loratadine, sildenafil. Simvastatin, gum base comprises at least one polymer selected from the Sumatriptan, acetaminophen, calcium carbonate, vitamin D, group consisting of polyesters, poly(ester-carbonates), poly ibuprofen, aspirin, alginic acid in combination with alumi carbonates, poly-ester amides, polyhydroxy alkanoates, num hydroxide and sodium bicarbonate, ondansetron, Tibo polypeptides, homopolymers of amino acids such as polyl lon, Rimonabant, Varenicline, allergenes, sitagliptin or any 35 ysine, proteins such as prolamin, and protein derivatives Such derivatives thereof, salts thereof, isomers thereof, combina as protein hydrolysates including a Zein hydrolysate, or any tions thereof or compounds comprising one or more of these. combination thereof. In an embodiment of the invention, said active ingredientis In an embodiment of the invention, said chewing gum selected from the group consisting of phytochemicals, such as granules are Substantially free of non-biodegradable poly resveratrol and anthocyanine; herbals. Such as green tea or 40 CS. thyme; antioxidants, such as polyphenols; micronutrients; In an embodiment of the invention, said compressed chew mouth moisteners, such as acids; throat soothing ingredients; ing gum is provided with an outer coating. appetite Suppressors; breath fresheners, such as Zinc com In an embodiment of the invention, said outer coating is pounds or copper compounds; diet Supplements; cold Sup selected from the group consisting of hard coating, soft coat pressors; cough Suppressors; vitamins, such as vitamin A, 45 ing and edible film-coating or any combination thereof. Vitamin C or vitamin E: minerals, such as chromium; metal In an embodiment of the invention, the chewing gum gran ions; alkaline materials, such as carbonates; salts; herbals, ules are formed through granulation and a following grinding. dental care agents, such as remineralisation agents, antibac When Smaller granules are needed, the chewing gum gran terial agents, anti-caries agents, plaque acid buffering agents, ules may first be granulated and Subsequently further grinded. tooth whiteners, stain removers or desensitizing agents; and 50 In an embodiment of the invention, the chewing gum gran combinations thereof. ules have been granulated to an average particle size of below In an embodiment of the invention, said active ingredientis 1500 um and further grinded to an average particle size of selected from the group consisting of di-peptides, tri-pep below 800 um. tides, oligo-peptides, deca-peptides, deca-peptide KSL, A grinding may preferably be carried out at a temperature deca-peptide KSL-W, amino acids, proteins, or any combi 55 of below 0°C., preferably below -10° C. nation thereof. In an embodiment of the invention, said chewing gum In an embodiment of the invention, said active ingredient composition comprises said gum base and one or more chew comprises probiotic bacteria, such as lactobacilli, bifidobac ing gum ingredients. teria, lactococcus, streptococcus, leuconostoccus, pediococ In an embodiment of the invention, said chewing gum CuS Or enterOCOCCuS. 60 granules comprises said gum base and one or more chewing In an embodiment of the invention, said active ingredient gum ingredients. comprises a prebiotic, Such as fructose, galactose, mannose, In an embodiment of the invention, at least a part of said insulin or Soy. one or more pharmaceutically active ingredients are mixed In an embodiment of the invention, said compressed chew into said chewing gum mixture prior to granulation. ing gum tablet comprises a center-fill. 65 In an embodiment of the invention, said chewing gum In an embodiment of the invention, said center-fill is a granules comprise at least a part of said one or more pharma liquid, a semi-liquid, or a solid composition. ceutically active ingredients. US 8,603,440 B2 11 12 In an embodiment of the invention, at least a part of the is obtained by applying gum base granules and bulk Sweet pharmaceutically ingredients are incorporated in at least a ener particles having comparable particle sizes. Small par part of the chewing gum granules. ticles of the pharmaceutically active ingredients are advanta In an embodiment of the invention, at least a part of the geously adhered to the larger particles by way of flavoring pharmaceutically active ingredients are adhered to bulk material or by way of a dry-binder. sweetener particles by way of flavor. In an embodiment of the invention, the chewing gum com In an embodiment of the invention, at least a part of the position is prepared by spraying one or more flavor materials pharmaceutically active ingredients are adhered to dry-binder onto the particles of bulk sweetenerand letting particles of the particles. pharmaceutically active ingredients adhere thereto. The pharmaceutically active ingredients have average par 10 ticle sizes which are relatively small, such as below 100 um. In an embodiment of the invention, the chewing gum com It has been found advantageous to bind the pharmaceutically position is prepared by spraying one or more flavor materials active ingredients to a dry-binder and/or to the Surrounding onto chewing gum granules and the particles of bulk Sweet chewing gum granules and/or bulk Sweetener particles. The enerand letting particles of the pharmaceutically active ingre dients adhere thereto. free flowability of the pharmaceutically active ingredients in 15 the chewing gum composition has thereby been reduced and In an embodiment of the invention, an amount of dry thereby the tendency to segregation has been reduced. A binder is used to adhere API to bulk sweetener. relatively even distribution of pharmaceutically active ingre In an embodiment of the invention, the used amount of dients in the chewing gum composition has been the result. dry-binder is in the range of 2% to 40%, preferably in the In an embodiment of the invention, said chewing gum range of 3% to 30%, and most preferably in the range of 5% granules comprise all of the one or more pharmaceutically to 20% by weight of the chewing gum composition in at least active ingredients. one of the modules of the compressed chewing gum tablet. In an embodiment of the invention, said first and/or second chewing gum composition is having an evenly distributed BRIEF DESCRIPTION OF THE DRAWINGS desired concentration of said one or more pharmaceutically 25 active ingredients. FIG.1a-1b illustrate a two-layer compressed tablet accord In an embodiment of the invention, said gum base com ing to an embodiment of the invention, prises two or more ingredients selected from the group con FIG. 2a-2b illustrate a three layer compressed tablet sisting of elastomers, elastomer plasticizers, resins, polyvinyl according to an embodiment of the invention, acetate, hydrogenated resins, polyterpene, fillers, fats and 30 FIG.2c-2d illustrate a four layer compressed tablet accord waxes, or any combination thereof. ing to an embodiment of the invention, In an embodiment of the invention, said chewing gum FIG.3a-3b illustrate a further two layer compressed tablet ingredients are selected from the group consisting of bulk according to an embodiment of the invention, Sweeteners, flavors, dry-binders, tabletting aids, anti-caking FIG. 4a-4b illustrate a further two layer compressed tablet agents, emulsifiers, antioxidants, enhancers, absorption 35 enhancers, pH control agents, high intensity Sweeteners, col according to an embodiment of the invention, ors, or any combination thereof. FIG.5a-5b illustrate a further two layer compressed tablet In an embodiment of the invention, the chewing gum gran according to an embodiment of the invention, ules comprise one or more chewing gum ingredients selected FIG. 6a-6d illustrate cross-sectional views of different from the group consisting of bulk Sweeteners, flavors, dry 40 compositions usable according to some embodiments of the binders, tabletting aids, anti-caking agents, emulsifiers, anti invention, and where oxidants, enhancers, absorption enhancers, pH control FIG. 7a-7b illustrate examples of one-layer compressed agents, or any combination thereof. tablets according to an embodiment of the invention. In an embodiment of the invention, one or more bulk sweet eners are provided as particles having average diameters 45 DETAILED DESCRIPTION OF THE INVENTION below 700 um, preferably below 500 um. In an embodiment of the invention, the particles of bulk With the present invention, as described in the following, sweetener have particle sizes in the range of 150 to 400 um. compressed chewing gum tablets comprising pharmaceuti In an embodiment of the invention, the chewing gum gran cally active ingredients and enhancers, e.g. for improving ules have average diameters below 1500 um, preferably 50 absorption of the pharmaceutically active ingredients, are below 1000 um, more preferably below 800 um, and most provided preferably below 600 um. It is obtained that the release of pharmaceutically active In an embodiment of the invention, the average particle size ingredients and associated enhancers can be synchronized in of the chewing gum granules is at most 5 times larger, pref advantageous ways. erably at most 3 times larger, and most preferably at most 2 55 AI (AI: Active ingredients) as used herein is used to cover times larger than the average particle size of the bulk Sweet e.g. API (API: pharmaceutically active ingredients) and ener particles. enhancers. In an embodiment of the invention, the chewing gum gran The word granule throughout this document should be ules and the bulk Sweetener particles have average particle understood as broadly as possibly being powder, particles, sizes deviating at most 600%, preferably at most 400% from 60 agglomerates or the like. Generally the four terms may be each other. used interchangeably. In an advantageous embodiment of the invention, there are The term “average diameter as used herein is defined as applied gum base granules and bulk Sweetener particles hav the diameter of a sphere having the same Volume as the ing comparable particle sizes. granule or particle, which is the consequence of that granules According to embodiments of the invention, powder seg 65 may possess almost any shape, and according to the definition regation is reduced and a more even distribution of pharma granules having the same Volume also have the same average ceutically active ingredients in the chewing gum composition diameter. US 8,603,440 B2 13 14 FIG. 1a illustrates a cross-section of a compressed multi The illustrated chewing gum tablet 30 comprises a gum modular chewing gum tablet according the invention and base incorporated chewing gum module 32 upon which illustrated in FIG. 1b. another gum base incorporated chewing gum base is The illustrated chewing gum tablet 10 comprises two arranged. chewing gum modules 11 and 12. 5 FIG. 4a illustrates a cross-section of a further compressed According to the illustrated embodiment, each module is multi-modular chewing gum tablet 40 according to an simply comprised by a layer. The multi-module tablet may in embodiment of the invention and illustrated in FIG. 4b from this embodiment be regarded as a two-layer chewing gum above. tablet 10. The tablet 40 differs somewhat from the other described The illustrated chewing gum tablet 10 may for example 10 tablets in the sense that the tablet comprises a compressed weigh approximately 1.3 gram and comprise a first GB-con GB-incorporated chewing gum module 42 forming a gum taining chewing gum module 11 and a second GB-containing center. The module 42 is encapsulated by a Surrounding mod module 12 (GB: gum base). ule 41. The illustrated tablet has an approximate diameter of 16 FIG. 5a illustrates a cross-section of a compressed multi mm and a thickness at the thickest point in the center of 15 modular chewing gum tablet 50 according to an embodiment approximately 7 mm. of the invention and illustrated in FIG. 5b from above. The two modules 11 and 12 are adhered to each other. According to the illustrated embodiment, showing a ring Different processes may be applied for the purpose. However, formed two layer tablet 50, a base chewing gum module 52 according to a preferred embodiment of the invention, the comprises a certain concentration of gum base, whereas the mutual adhering between the two layers is obtained by the other layer comprises another content of gum base 51. compression of one module 11 onto the other 12. FIGS. 6a-6c illustrate compositions of granules according According to an embodiment of the invention, the illus to embodiments of the invention, ready for being compressed trated chewing gum tablet 10 may be provided with a coating, to a module in a chewing gum tablet according to embodi e.g. a film coating. ments of the invention. In FIG. 6a the composition consists of It should be noted that various concentrations of gum base 25 granules 60 uniformly shaped and sized. FIG. 6c illustrates a in the different modules (here: layers) may be applied within composition of granules 62, 63, 64, 65 with varying shapes the scope of the invention. and sizes. The modules may for instance comprise compressible A composition of a mixture of chewing gum granules and chewing gum ingredients, for example Sweeteners and fla bulk sweetener with flavor-"glued, i.e. adhered, AI may e.g. Vors, more or less pre-processed for the purpose of facilitating 30 look as FIG. 6c, in which e.g. 62 and 63 could be chewing a true compression. Other optional ingredients to be empha gum granules and e.g. 64 and 65 could be agglomerated bulk sized here may e.g. comprise pharmaceutically active ingre sweetener with flavor-"glued” AI. dients. Further a composition may look as in FIG. 6c wherein e.g. In other applications, e.g. for the purpose of establishing 63 is chewing gum granules with or without AI and 62, 64, 65 different release profiles the different modules may comprise 35 may be other typical chewing gum ingredients such as bulk different content of gum base. sweetener, flavor, filler, etc. The tablet may moreover comprise (not shown) one or FIG. 6d illustrates a composition like in FIG. 6c, wherein several barrier layers adapted for establishment of a barrier an improved size distribution has been obtained in order to between inter-reacting ingredients, such as certain acids and avoid segregation. With too large differences in the granule flavors. 40 sizes segregation may be a problem, in that the Smaller par FIG. 2a illustrates a cross-section of a compressed multi ticles will tend to move more easily in a composition than the modular chewing gum tablet according to an embodiment of larger particles and hence a concentration of e.g. an active the invention and illustrated in FIG. 2b from above. ingredient in a composition may be in a risk of being very The illustrated embodiment 20 comprises a three-module different in a sample taken from the composition. chewing gum of which the each of the layers 21, 22, and 23 45 FIG. 6b illustrates a composition comprising a mixture of optionally comprise a gum base incorporated chewing gum chewing gum granules 60 and agglomerated bulk Sweetener module having a certain gum base concentration. As an with flavor-"glued API 61, wherein the size of the chewing example layers 21 and 22 may contain gum base and layer 23 gum granules 60 and the agglomerated bulk Sweetener with may be a Substantially gum base-free chewing gum module. flavor-"glued API 61 is essentially the same. A layer without gum base, which could be chewing gum 50 FIGS. 6a-6c are illustrative examples only of how compo module 23, may for example comprise compressed chewing sitions may look according to embodiments of the invention. gum ingredients, such as Sweeteners, flavor, freeze-dried fruit As should be apparent from the content of the description, the etc. compositions as mentioned herein may comprise active Modules containing gum base, here the two modules 21 ingredients and gum base in different layers, wherein the AIS and 22, may advantageously comprise different gum base 55 may be incorporated in the granules or added to the compo content for the purpose of providing a desired release profile, sition outside the granules as long as the gum base content is whereas a non-GB module, here module 23, may ensure a fast different and a desired release profile may be achieved. release of an active ingredient or simply add an amount of FIGS. 7a-7b illustrate examples of one-layer compressed bulk Sweetener or other chewing gum ingredients, which are chewing gum tablets 70 according to embodiments of the quickly released when the tablet is chewed. 60 invention. FIG. 7a illustrates a circular shape of a tablet FIGS.2c and 2d illustrate a cross-section of a compressed according to an embodiment of the invention, while FIG.7b multi modular chewing gum tablet according to an embodi illustrates a trilateral shape of a one-layer compressed chew ment of the invention with the same possibilities as explained ing gum tablet according to an embodiment of the invention. above with reference to FIGS. 2a and 2b. The formulations, applied pharmaceutically active ingre FIG. 3a illustrates a cross-section of a compressed multi 65 dients, examples of compositions and layers given herein are modular chewing gum tablet 30 according the invention and exemplary and only given for the purpose of evaluating and illustrated in FIG. 3b from above. explaining different features of the invention. Compositions US 8,603,440 B2 15 16 and the combinations of layers may be varied significantly pinene, and/or d-limonene, natural terpene resins, glycerol within the scope of the invention. Specific variations and esters of gum rosins, tall oil rosins, wood rosins or other details with respect to ingredients, formulations and compo derivatives thereof such as glycerol esters of partially hydro sitions within the scope of the invention are given below. genated rosins, glycerol esters of polymerized rosins, glyc In accordance with the general principles in manufacturing erol esters of partially dimerised rosins, pentaerythritol esters a chewing gum tablet within the scope of the invention, varia of partially hydrogenated rosins, methyl esters of rosins, par tions of different suitable ingredients are listed and explained tially hydrogenated methyl esters of rosins or pentaerythritol below. esters of rosins and combinations thereof. Chewing gum of the present invention typically comprises Materials to be used for encapsulation methods may e.g. a water-soluble portion, a water-insoluble chewable gum base 10 include Gelatine. Wheat protein, Soya protein, Sodium portion and flavoring agents. The water-soluble portion dis caseinate, Caseine, Gum arabic, Mod. Starch, Hydrolyzed sipates with a portion of the flavoring agent over a period of starches (maltodextrines), Alginates, Pectin, Carregeenan, time during chewing. The gum base portion is retained in the Xanthan gum, Locus bean gum, Chitosan, Bees wax, Cande mouth throughout the chew. The term chewing gum refers to lilla wax, Carnauba wax, Hydrogenated vegetable oils, Zein both a chewing and bubble type gum in its general sense. 15 and/or Sucrose. The gum base is the masticatory Substance of the chewing Examples of generally non-biodegradable synthetic resins gum, which imparts the chew characteristics to the final prod include polyvinyl acetate, vinyl acetate-vinyl laurate copoly uct. The gum base typically defines the release profile of mers and mixtures thereof. Examples of non-biodegradable flavors and Sweeteners and plays a significant role in the gum synthetic elastomers include, but are not limited to, synthetic product. elastomers listed in Food and Drug Administration, CFR, The insoluble portion of the gum typically may contain any Title 21, Section 172,615, the Masticatory Substances, Syn combination of elastomers, vinyl polymers, elastomer plasti thetic) such as polyisobutylene. e.g. having a gel permeation cizers, waxes, softeners, fillers and other optional ingredients chromatography (GPC) average molecular weight in the Such as colorants and antioxidants. range of about 10,000 to 1,000,000 including the range of The composition of gum base formulations can vary Sub 25 50,000 to 80,000, isobutylene-isoprene copolymer (butyl stantially depending on the particular product to be prepared elastomer), Styrene-butadiene copolymers e.g. having sty and on the desired masticatory and other sensory character rene-butadiene ratios of about 1:3 to 3:1, polyvinyl acetate istics of the final product. However, typical ranges (% by (PVA), e.g. having a GPC average molecular weight in the weight) of the above gum base components are: 5 to 80% by range of 2,000 to 90,000 such as the range of 3,000 to 80,000 weight elastomeric compounds, 5 to 80% by weight elas 30 including the range of 30,000 to 50,000, where the higher tomer plasticizers, 0 to 40% by weight of waxes, 5 to 35% by molecular weight polyvinyl acetates are typically used in weight softener, 0 to 50% by weight filler, and 0 to 5% by bubblegum base, polyisoprene, polyethylene, vinyl acetate weight of miscellaneous ingredients such as antioxidants, vinyl laurate copolymer e.g. having a vinyl laurate content of colourants, etc. The gum base may comprise about 5 to about about 5 to 50% by weight such as 10 to 45% by weight of the 95 percent, by weight, of the chewing gum, more commonly 35 copolymer, and combinations hereof. the gum base comprises 10 to about 60 percent, by weight, of The elastomers (rubbers) employed in the gum base may the gum. vary depending upon various factors such as the type of gum Elastomers provide the rubbery, cohesive nature to the base desired, the texture of gum composition desired and the gum, which varies depending on this ingredient’s chemical other components used in the composition to make the final structure and how it may be compounded with other ingredi 40 chewing gum product. The elastomer may be any water ents. Elastomers Suitable for use in the gum base and gum of insoluble polymer known in the art, and includes those gum the present invention may include natural or synthetic types. polymers utilized for chewing gums and bubblegums. Illus Elastomer plasticizers vary the firmness of the gum base. trative examples of Suitable polymers in gum bases include Their specificity on elastomer inter-molecular chain breaking both natural and synthetic elastomers. For example, those (plasticizing) along with their varying softening points cause 45 polymers which are Suitable in gum base compositions varying degrees of finished gum firmness and compatibility include, without limitation, natural Substances (of vegetable when used in base. This may be important when one wants to origin) Such as chicle gum, natural rubber, crown gum, nis provide more elastomeric chain exposure to the alkane chains pero, rosidinha, jelutong, perillo, niger gutta, tunu, balata, of the waxes. guttapercha, lechi capsi, Sorva, gutta kay, and the like, and The elastomer compounds may be of natural origin but are 50 mixtures thereof. Examples of synthetic elastomers include, preferably of synthetic origin, preferably synthetic polyes without limitation, styrene-butadiene copolymers (SBR), terS. polyisobutylene, isobutylene-isoprene copolymers, polyeth It is noted that gum base or gum granules may also include ylene, polyvinyl acetate and the like, and mixtures thereof. components typically referred to as chewing gum ingredients. It is common in the industry to combine in a gum base a The chewing gum may, according to embodiments of the 55 synthetic elastomer having a high molecular weight and a invention, comprise conventionally non-biodegradable poly synthetic elastomer having a low molecular weight. mers, such as natural resins, synthetic resins and/or synthetic Examples of Such combinations are polyisobutylene and sty or natural elastomers. rene-butadiene, polyisobutylene and polyisoprene, poly According to an embodiment of the invention, at least a isobutylene and isobutylene-isoprene copolymer (butyl rub part of the polymers of the chewing gum are biodegradable. 60 ber) and a combination of polyisobutylene, styrene-butadiene In an embodiment of the invention, the chewing gum may copolymerandisobutylene isoprene copolymer, and all of the comprise combinations of biodegradable polymers and poly above individual synthetic polymers in admixture with poly mers generally regarded as non-biodegradable. Such as natu vinyl acetate, vinyl acetate-vinyl laurate copolymers, respec ral resins, synthetic resins and/or synthetic/natural elas tively and mixtures thereof. tOmerS. 65 Examples of natural resins are: Natural rosin esters, often In an embodiment of the invention, said natural resin com referred to as ester gums including as examples glycerol prises terpene resins, e.g. derived from alpha-pinene, beta esters of partially hydrogenated rosins, glycerol esters of US 8,603,440 B2 17 18 polymerised rosins, glycerolesters of partially dimerized ros ingredients and especially the active ingredient typically ins, glycerol esters of tally oil rosins, pentaerythritol esters of being quite Vulnerable to for example high temperatures. partially hydrogenated rosins, methyl esters of rosins, par In further embodiments of the present invention, a chewing tially hydrogenated methyl esters of rosins, pentaerythritol gum may also be provided with an outer coating, which may esters of rosins, synthetic resins such asterpene resins derived 5 be a hard coating, a softcoating, a film coating, or a coating of from alpha-pinene, beta-pinene, and/or d-limonene, and any type that is known in the art, or a combination of Such natural terpene resins. coatings. The coating may typically constitute 0.1 to 75% by The chewing gum according to embodiments of the inven weight of a coated chewing gum piece. tion may be provided with an outer coating. The applicable One preferred outer coating type is a hard coating, which hard coating may be selected from the group comprising of 10 Sugar coating and a Sugarless coating and a combination term is including Sugar coatings and Sugar-free (or Sugarless) thereof. The hard coating may e.g. comprise 50 to 100% by coatings and combinations thereof. The object of hardcoating weight of a polyol selected from the group consisting of is to obtaina Sweet, crunchy layer, which is appreciated by the sorbitol, maltitol, mannitol, xylitol, erythritol, lactitol and consumer and to protect the gum centers. In a typical process Isomalt and variations thereof. In an embodiment of the 15 of providing the chewing gum centers with a protective Sugar invention, the outer coating is an edible film comprising at coating the gum centers are successively treated in Suitable least one component selected from the group consisting of an coating equipment with aqueous solutions of crystallizable edible film-forming agent and a wax. The film-forming agent Sugar Such as Sucrose or dextrose, which, depending on the may e.g. be selected from the group comprising cellulose stage of coating reached, may contain other functional ingre derivative, a modified Starch, a dextrin, gelatine, shellac, gum dients, e.g. fillers, colors, etc. arabic, Zein, a vegetable gum, a synthetic polymer and any In one presently preferred embodiment, the coating agent combination thereof. In an embodiment of the invention, the applied in a hard coating process is a Sugarless coating agent, outer coating comprises at least one additive component e.g. a polyol including as examples Sorbitol, maltitol, manni selected from the group comprising of a binding agent, a tol. Xylitol, erythritol, lactitol and isomalt or e.g. a mono-di moisture-absorbing component, a film-forming agent, a dis 25 saccharide including as example trehalose. persing agent, an antisticking component, a bulking agent, a Or alternatively a Sugar-free soft coating e.g. comprising flavoring agent, a coloring agent, a pharmaceutically or cos alternately applying to the centers a syrup of a polyol or a metically active component, a lipid component, a wax com mono-di-saccharide, including as examples Sorbitol, maltitol, ponent, a Sugar, an acid and an agent capable of accelerating mannitol. Xylitol, erythritol, lactitol, isomalt and trehalose. the after-chewing degradation of the degradable polymer. 30 In further useful embodiments, a film coating is provided Generally, the ingredients may be mixed by first melting by film-forming agents such as a cellulose derivative, a modi the gum base and adding it to the running mixer. Colors, fied starch, a dextrin, gelatine, Zein, shellec, gum arabic, a active agents and/or emulsifiers may also be added at this Vegetable gum, a synthetic polymer, etc. or a combination time. A softener Such as glycerin may also be added at this thereof. time, along with syrup and a portion of the bulking agent/ 35 In an embodiment of the invention, the outer coating com sweetener. Further portions of the bulking agent/sweetener prises at least one additive component selected from the may then be added to the mixer. A flavoring agent is typically group comprising a binding agent, a moisture-absorbing added with the final portion of the bulking agent/sweetener. A component, a film-forming agent, a dispersing agent, an anti high-intensity sweetener is preferably added after the final Sticking component, a bulking agent, a flavoring agent, a portion of bulking agent and flavor has been added. 40 coloring agent, a pharmaceutically or cosmetically active The entire mixing procedure typically takes from five to component, a lipid component, a wax component, a Sugar, fifteen minutes, but longer mixing times may sometimes be and an acid. required. Those skilled in the art will recognize that many A coated chewing gum center according to embodiments variations of the above-described procedure may be followed. of the invention may have any form, shape or dimension that Including the one-step method described in US patent appli 45 permits the chewing gum center to be coated using any con cation 2004/01 15305 hereby incorporated as reference. ventional coating process. Chewing gums are formed by extrusion, compression, rolling It should however be noted that application of different and may be centre filled with liquids and/or solids in any coating should be done with care as compressed chewing gum form. tablets may be negatively affected by direct contact with When manufacturing a compressed chewing gum tablet 50 moisture or water. another method is applied, which is basically very different The composition of gum base formulations can vary Sub than the above described, but may broadly be described as an stantially depending on the particular product to be prepared initial conventional mixing of the gum base, as above and on the desired masticatory and other sensory character described, followed by a granulation of the obtained gum istics of the final product. However, typical ranges of the base mix. The obtained chewing gum granules may then be 55 above gum base components are: 5 to 80% by weight of mixed with further chewing gum ingredients, such as Sweet elastomeric compounds, 5 to 80% by weight of elastomer eners and flavor. This final granule mix may then be com plasticizers, 0 to 40% by weight of waxes, 5 to 35% by weight pressed under high pressure (typically when applying cool of softener, 0 to 50% by weight offiller, and 0 to 5% by weight ing) into a chewing gum tablet. For each compression a layer of miscellaneous ingredients such as antioxidants, colorants, is made and in this way it is possible to make multi-layered 60 etc. The gum base may comprise about 5 to about 95% by chewing gums, such as two, three or four layers, wherein each weight of the chewing gum, more commonly; the gum base layer may include an individual composition, i.e. different comprises 10 to about 60% by weight of the gum. active ingredients may be used for medical purposes or dif Elastomers provide the rubbery, cohesive nature to the ferent colors may be used for visual purposes, etc. gum, which varies depending on this ingredient’s chemical This type of chewing gum has been widely used especially 65 structure and how it may be compounded with other ingredi within a segment of medical chewing gum due to the thereto ents. Elastomers Suitable for use in the gum base and gum of related relatively careful way of handling the chewing gum the present invention may include natural or synthetic types. US 8,603,440 B2 19 20 Elastomer plasticizers vary the firmness of the gum base. at least one polyester that is produced through a reaction of at Their specificity on elastomer inter-molecular chain breaking least one alcohol chosen from the group consisting of glyc (plasticizing) along with their varying softening points cause erol, propylene glycol, and 1.3 butylene diol, and at least one varying degrees of finished gum firmness and compatibility acid chosen from the group consisting of fumaric acid, adipic when used in gum base. This may be important when one 5 acid, malic acid. Succinic acid, and tartaric acid, the polyester wants to provide more elastomeric chain exposure to the being end-capped with a monofunctional ingredient selected alkanic chains of the waxes. from the group consisting of alcohols, acids, chlorides, and If desired, conventional elastomers or resins may be esters, supplemented or substituted by biodegradable polymers. and further such as can be found in e.g. U.S. Pat. No. 6,773, Biodegradable polymers that may be used in the chewing 10 730, U.S. Pat. No. 6,613,363, U.S. Pat. No. 6,194,008, U.S. Pat. No. 5,580,590, U.S. Pat. No. 6,858,238, U.S. Pat. No. gum of the present invention may be homopolymers, copoly 6,017,566, U.S. Pat. No. 6,013,287, and U.S. Pat. No. 5,800, mers or terpolymers, including graft- and block-polymers. 848, which are all hereby incorporated by reference. Useful biodegradable polymers, which may be applied as The polyesters formed on the basis of di- or polyfunctional gum base polymers in the chewing gum of the present inven 15 acids and di- or polyfunctional alcohols may be produced tion, may generally be prepared by step-growth polymeriza according to known methods, one of which includes US2007/ tion of di-, tri- or higher-functional alcohols or esters thereof 043200, hereby incorporated by reference. with di-, tri- or higher-functional aliphatic or aromatic car The prolamine may e.g. be selected from the group con boxylic acids or esters thereof. Likewise, also hydroxy acids sisting of Zein, corn gluten meal, wheat gluten, gliadin, glu or anhydrides and halides of polyfunctional carboxylic acids tenin and any combination thereof. Methods of providing may be used as monomers. The polymerization may involve such a polymer are disclosed in US2004/001903, hereby direct polyesterification or transesterification and may be incorporated by reference. catalyzed. Examples of such proteinbased compounds include but are The usually preferred polyfunctional alcohols contain 2 to not limited to prolamine, Zein, corn gluten meal, wheat glu 100 carbon atoms as for instance polyglycols and polyglyc 25 ten, gliadin, glutenin and combinations thereof. erols. Such Suitable biodegradable gum base polymers include Gum base polymers may both be resinous and elastomeric polyesters, polycarbonates, polyesteramides, polyesterure polymers. thanes, polyamides, prolamine, and combinations thereof. In the polymerization of a gum base polymer for use in the Carbonates may typically be co-polymerised with esters. chewing gum of the present invention, Some applicable 30 Some typically preferred cyclic carbonates, which may be examples of alcohols, which may be employed as such or as used as starting material, may e.g. comprise trimethylene derivatives thereof, include polyols such as ethylene glycol, carbonate, 2,2-dimethyltrimethylene carbonate, 2-methyltri 1.2-propanediol. 1,3-propanediol. 1,3-butanediol. 1,4-bu methylene carbonate, 3-methyltrimethylene carbonate, 2,3- tanediol, 1.6-hexanediol, diethylene glycol, 1,4-cyclohex dimethyltrimethylene carbonate, 2,4-dimethyltrimethylene anediol. 1,4-cyclohexanedimethanol, neopentylglycol, glyc 35 carbonate, 2,3,4-trimethyltrimethylene carbonate, 2,3,3,4- erol, trimethylolpropane, pentaerythritol, Sorbitol, mannitol, tetramethyltrimethylene carbonate, etc. etc. In some embodiments, Suitable polyesteramides can be Suitable examples of environmentally or biologically constructed from monomers of the following groups: dialco degradable chewing gum base polymers, which may be hols, such as ethylene glycol, 1,4-butanediol. 1,3-pro applied in accordance with the gum base of the present inven 40 panediol, 1.6-hexanediol diethylene glycol and others; and/or tion, include degradable polyesters, polycarbonates, polyes dicarboxylic acid, such as oxalic acid. Succinic acid, adipic ter amides, polyesterurethanes, polyamides, prolamine, acid and others, including those in the form of their respective polypeptides, homopolymers of amino acids such as polyl esters (methyl, ethyl, etc.); and/or hydroxycarboxylic acids ysine, and proteins including derivatives hereof Such as e.g. and lactones, such as caprolactone and others; and/or amino protein hydrolysates including a Zein hydrolysate. 45 alcohols, such as ethanolamine, propanolamine, etc.; and/or Polyesters which may be applied in accordance with the cyclic lactams, such as .epsilon.-caprolactam or laurolactam, gum base of the present invention may e.g. be as seen in EP 1 etc.; and/or omega.-aminocarboxylic acids, such as ami 545 234 or EP 0711506 as incorporated herein by reference. nocaproic acid, etc.; and/or mixtures (1:1 salts) ofdicarboxy Further polymers which may be used in the gum base lic acids such as adipic acid, Succinic acid etc., and diamines according to embodiments of the invention comprise: 50 Such as hexamethyl enediamine, diaminobutane, etc. enzymatically hydrolyzed Zein, plasticized poly(D.L-lactic In the case where the polymer mixture is based extensively acid) and poly(D.L-lactic acid-co-glycolic acid), polyhy on thermoplastic starch and an aromatic polyester, an ali droxyalkanoates having side chain lengths of C to Co. poly phatic-aromatic copolyester, or a polyesteramide, it may be (lactic acid) copolymers selected from the group consisting of advantageous to add an aliphatic polyester or copolyester, poly(lactic acid-dimer fatty acid-oxazoline) copolymers and 55 Such as polycaprolactone, for example, as a further compo poly(lactic acid-diol-urethane) copolymers, nent. As an example of this there may be mentioned a polymer at least one polyester wherein the polyester includes mono mixture consisting of thermoplastic starch, at least one poly mers selected from the group consisting of lactic acid, lactide, ethylene terephthalate (PET) or a polyalkylene terephthalate, glycolic acid, glycolide, citric acid, adipic acid, caprolactone, and polycaprolactone. Other examples of aliphatic polyesters ethylene oxide, ethylene glycol, propylene oxide, and propy 60 or copolyesters are polylactic acid, polyhydroxybutyric acid, lene glycol, and combinations thereof, polyhydroxybutyric acid-hydroxyvaleric acid copolymer, at least one polyester that is produced through a reaction of and/or mixtures thereof. glycerol and at least one acid chosen from the group consist Suitable polyesters may be obtained through polyconden ing of citric acid, fumaric acid, adipic acid, malic acid, suc sation polymerisation or ring-opening polymerisation reac cinic acid, Suberic acid, sebacic acid, dodecanedioic acid, 65 tions. Some preferred polyesters include those polymerised glucaric acid, glutamic acid, glutaric acid, azelaic acid, and from at least one carboxylic acid and at least one aliphatic di tartaric acid, or polyfunctional alcohols. The carboxylic acids may include US 8,603,440 B2 21 22 aromatic dicarboxylic acids and aliphatic di- or polyfuncional diethylene glycol, 1.4-cyclohexanediol, 1.4-cyclohex carboxylic acids. In some preferred embodiments, the major anedimethanol, neopentyl glycol, glycerol, trimethylolpro ity of the carboxylic acids are aliphatic. pane, pentaerythritol, Sorbitol, mannitol, etc. For the purpose Some of the preferred polyesters according to embodi of illustration and not limitation, some examples of alcohol ments of the invention may e.g. be prepared by step-growth 5 derivatives include triacetin, glycerol palmitate, glycerol polymerization of di-, tri- or higher-functional alcohols or sebacate, glycerol adipate, tripropionin, etc. esters thereof with di-, tri- or higher-functional aliphatic or Additionally, with regard to polyesters polymerized from aromatic carboxylic acids or esters thereof. Likewise, also alcohols orderivatives thereof and carboxylic acids orderiva hydroxy acids or anhydrides and halides of polyfunctional tives thereof, chain-stoppers sometimes used are monofunc carboxylic acids may be used as monomers. The polymeriza 10 tional compounds. They are preferably either monohydroxy tion may involve direct polyesterification or transesterifica alcohols containing 1-20 carbon atoms or monocarboxylic tion and may be catalyzed. Use of branched monomers Sup acids containing 2-26 carbon atoms. General examples are presses the crystallinity of the polyester polymers. Mixing of medium or long-chain fatty alcohols or acids, and specific dissimilar monomer units along the chain also suppresses examples include monohydroxy alcohols such as methanol, crystallinity. To control the reaction and the molecular weight 15 ethanol, butanol, hexanol, octanol, etc., and lauryl alcohol, of the resulting polymer it is possible to stop the polymer myristyl alcohol, cetyl alcohol, Stearyl alcohol, Stearic alco chains by addition of monofunctional alcohols oracids and/or hol, etc., and monocarboxylic acids such as acetic, lauric, to utilize a stoichiometric imbalance between acid groups and myristic, palmitic, Stearic, arachidic, cerotic, dodecylenic, alcohol groups orderivatives of either. Also the adding of long palmitoleic, oleic, linoleic, linolenic, erucic, benzoic, naph chain aliphatic carboxylic acids or aromatic monocarboxylic thoic acids and Substituted naptholic acids, 1-methyl-2 naph acids may be used to control the degree of branching in the thoic acid and 2-isopropyl-1-naphthoic acid, etc. polymer and conversely multifunctional monomers are Typically, an acid catalyst or a transesterification catalyst Sometimes used to create branching. Moreover, following the may be used in Such polyester polymerization processes, and polymerization monofunctional compounds may be used to non-limiting examples of those are the metal catalysts such as end cap the free hydroxyl and carboxyl groups. 25 acetates of manganese, Zinc, calcium, cobalt or magnesium, Examples of aliphatic di- or polyfunctional carboxylic and antimony(III) oxide, germanium oxide or halide and tet acids, which may be applied as monomers of Suitable poly raalkoxygermanium, titanium alkoxide, Zinc or aluminum esters include oxalic, malonic, citric, succinic, malic, tartaric, salts. fumaric, maleic, glutaric, glutamic, adipic, glucaric, pimelic, In a preferred embodiment of the invention, the polyesters Suberic, azelaic, Sebacic, dodecanedioic acid, etc. Likewise, 30 can for example include copolymers containing any combi specific examples of aromatic polyfunctional carboxylic nation of the monomers lactic acid, lactide, glycolic acid, acids may be terephthalic, isophthalic, phthalic, trimelitic, glycolide, citric acid, adipic acid, caprolactone, ethylene pyromellitic and naphthalene 1,4-, 2.3-, 2,6-dicarboxylic oxide, ethylene glycol, propylene oxide, propylene glycol acids and the like. Some preferred polyesters are disclosed in and combinations thereof. CA2523510, hereby included by reference. 35 Examples of Suitable polyesters obtainable by ring-open In a preferred embodiment, aliphatic dicarboxylic acids ing polymerization include polyesters comprising combina applied in the polyesters are selected from aliphatic dicar tions of cyclic monomers including the following: boxylic acids having from 4 to 12 carbons, such as Succinic D.L-lactidefe-caprolactone, acid, glutaric acid, 2-methylglutaric acid, 3-methylglutaric D.L-lactide/TMC acid, 2,2-dimethylglutaric acid, adipic acid, pimelic acid, 40 D.L-lactide? 8-valerolactone Suberic acid, azelaic acid and sebacic acid, higher homo D.L-lactide? dioxanone logues and stereoisomers and mixtures thereof. Preferred ali D.L-lactide phatic dicarboxylic acids in this embodiment are Succinic L-lactidefe-caprolactone acid, glutaric acid, adipic acid, pimelic acid, azelaic acid and sebacic acid, and mixtures thereof. 45 L-lactidefö-Valerolactone In an embodiment, aromatic dicarboxylic acids applied in L-lactidefodioxanone the polyesters contain two carboxyl groups which are bound L-lactide to one aromatic system. Preferably, the aromatic system is D.L-lactide/glycolide/e-caprolactone carboaromatic, such as phenyl or naphthyl. In the case of D.L-lactide/glycolide/TMC polynuclear aromatics, the two carboxyl groups may be 50 D.L-lactide/glycolide/8-valerolactone bound to the same ring or different rings. The aromatic system D.L-lactide/glycolide? dioxanone can also have one or more alkyl groups, for example methyl D.L-lactide/glycolide groups. The aromatic dicarboxylic acid is then generally L-lactide/glycolide/e-caprolactone selected from aromatic dicarboxylic acids having from 8 to 12 L-lactide/glycolide/TMC carbons, such as phthalic acid, isophthalic acid, terephthalic 55 L-lactide/glycolide/8-valerolactone acid, 1.5- and 2.6-naphthalenedicarboxylic acid. Preferred L-lactide/glycolide? dioxanone aromatic dicarboxylic acids in this embodiment are tereph L-lactide/glycolide thalic acid, isophthalic acid and phthalic acid and mixtures glycolide/e-caprolactone thereof. glycolide/TMC Furthermore, some usually preferred polyfunctional alco 60 glycolide/8-valerolactone hols suitable for preparing advantageous polyesters accord glycolide? dioxanone ing to embodiments of the invention contain 2 to 100 carbon glycolide atoms as for instance polyglycols and polyglycerols. Suitable D.L-lactide/L-lactidefe-caprolactone examples of alcohols, which may be employed in the poly merization process as such or as derivatives thereof, includes 65 D.L-lactide/L-lactidefö-Valerolactone polyols such as ethylene glycol, 1.2-propanediol. 1,3-pro D.L-lactide/L-lactide? dioxanone panediol. 1,3-butanediol. 1,4-butanediol, 1.6-hexanediol. D.L-lactide/L-lactide US 8,603,440 B2 23 24 D.L-lactide/L-lactide/glycolide/e-caprolactone To soften the gum base further and to provide it with D.L-lactide/L-lactide/glycolide/TMC water-binding properties, which confer to the gum base a D.L-lactide/L-lactide/glycolide/8-valerolactone pleasant Smooth Surface and reduce its adhesive properties, D.L-lactide/L-lactide/glycolide/dioxanone one or more emulsifiers is/are usually added to the composi D.L-lactide/L-lactide/glycolide tion, typically in an amount of 0 to 18% by weight, preferably Some examples of the resulting polyester gum base poly 0 to 12% by weight of the gum base. Useful emulsifiers can mers include poly(L-lactide-co-trimethylenecarbonate); poly include, but are not limited to, glyceryl monostearate, propy (L-lactide-co-epsilon-caprolactone); poly(D.L-lactide-co lene glycol monostearate, mono- and diglycerides of edible trimethylenecarbonate); poly(D.L-lactide-co-epsilon fatty acids, lactic acid esters and acetic acid esters of mono caprolactone); poly(meso-lactide-co 10 and diglycerides of edible fatty acids, acetylated mono and trimethylenecarbonate); poly(mesolactide-co-epsilon diglycerides, Sugar esters of edible fatty acids, Na-, K-Mg caprolactone); poly(glycolide-cotrimethylenecarbonate); and Ca-stearates, lecithin, hydroxylated lecithin and the like poly(glycolide-co-epsilon-caprolactone), etc. Suitable poly and mixtures thereof are examples of conventionally used esters are also disclosed in WO 2004/028270, hereby incor emulsifiers which can be added to the chewing gum base. In porated by reference. 15 case of the presence of a biologically or pharmaceutically In an embodiment, the polyesters may be obtained by the active ingredient as defined below, the formulation may com reaction between at least one dimer acid and at least one prise certain specific emulsifiers and/or solubilisers in order glycol or alcohol. Such glycols can include, for example, to disperse and release the active ingredient. glycerin, propylene glycol, ethylene glycol, poly(ethylene Waxes and fats are conventionally used for the adjustment glycol), poly(propylene glycol), poly(ethylene glycol-co of the texture and for softening of the chewing gum base when propylene glycol), while Such alcohols can include, for preparing chewing gum bases. In connection with the present example, methanol, ethanol, propanol, and butanol, and Such invention, any conventionally used and Suitable type of natu dimer acids can include, for example, adipic acid and citric ral and synthetic wax and fat may be used, such as for instance acid, etc. rice bran wax, polyethylene wax, petroleum wax (refined Some specific examples of suitable polyesters include poly 25 paraffin and microcrystalline wax), Sorbitan monostearate, (lactic acid), polylactide, poly(glycolic acid), polyglycolide, tallow, propylene glycol, paraffin, beeswax, carnauba wax, poly(citric acid), polycaprolactone, polyhydroxyalkanoate, candelilla wax, cocoa butter, degreased cocoa powder and and combinations thereof. any Suitable oil or fat, as e.g. completely or partially hydro Some Suitable prolamines include Zein, corn gluten meal, genated vegetable oils or completely or partially hydroge wheat gluten, gliadin, glutenin and combinations thereof. 30 nated animal fats. Moreover, blends of prolamine with polyester such as those A chewing gum base formulation may, if desired, include disclosed in U.S. Pat. No. 6,858.238, hereby included by one or more fillers/texturisers including as examples, magne reference, may be useful in chewing gum according to sium and calcium carbonate, sodium Sulphate, ground lime embodiments of the invention. stone, silicate compounds such as magnesium and aluminum Agglomeration which may be used on e.g. tablet material 35 silicate, kaolin and clay, aluminum oxide, silicium oxide, talc, and active ingredients in an embodiment of the invention may titanium oxide, mono-, di- and tri-calcium phosphates, cellu be performed for instance by fluid bed agglomeration, a pro lose polymers, such as wood, and combinations thereof. cess known to the person skilled in the art. In addition to a water insolublegum base portion, a typical The chewing gum may include any component known in chewing gum includes a water Soluble bulk portion and one or the chewing gum art. For example, the chewing gum may 40 more flavoring agents. The water-soluble portion may include include elastomers, bulking agents, waxes, elastomer Sol bulk Sweeteners, high-intensity Sweeteners, flavoring agents, vents, emulsifiers, plasticizers, fillers, and mixtures thereof. softeners, emulsifiers, colors, acidulants, buffering agents, The chewing gum according to embodiments of the inven fillers, antioxidants, and other components that provide tion may comprise coloring agents. According to an embodi desired attributes. ment of the invention, the chewing gum may comprise color 45 Combinations of Sugar and/or non-Sugar Sweeteners can be agents and whiteners such as FD&C-type dyes and lakes, fruit used in the chewing gum formulation processed in accor and vegetable extracts, titanium dioxide and combinations dance with the invention. Additionally, the softener may also thereof. provide additional Sweetness Such as aqueous Sugar oralditol Further useful chewing gum base components include anti Solutions. oxidants, e.g. butylated hydroxytoluene (BHT), butyl 50 Useful Sugar Sweeteners are saccharide-containing com hydroxyanisol (BHA), propylgallate and tocopherols, and ponents commonly known in the chewing gum art including, preservatives. but not limited to. Sucrose, dextrose, maltose, dextrins, treha A gum base formulation may, in accordance with the lose, D-tagatose, dried invert Sugar, fructose, levulose, galac present invention, comprise one or more softening agents e.g. tose, corn syrup Solids, and the like, alone or in combination. sucrose esters including those disclosed in WO 00/25598, 55 Sorbitol can be used as a non-sugar Sweetener. Other useful which is incorporated herein by reference, tallow, hydroge non-Sugar Sweeteners include, but are not limited to, other nated tallow, hydrogenated and partially hydrogenated veg Sugar alcohols such as mannitol, Xylitol, hydrogenated Starch etable oils, cocoa butter, degreased cocoa powder, glycerol hydrolysates, maltitol, isomaltol, erythritol, lactitol and the monostearate, glyceryl triacetate, lecithin, mono-, di- and like, alone or in combination. triglycerides, acetylated monoglycerides, lanolin, sodium 60 High-intensity artificial Sweetening agents can also be used Stearate, potassium Stearate, glyceryl lecithin, propylene gly alone or in combination with the above sweeteners. Preferred col monostearate, glycerine, fatty acids (e.g. Stearic, palmitic, high-intensity Sweeteners include, but are not limited to oleic and linoleic acids) and combinations thereof. As used Sucralose, aspartame, salts of acesulfame, alitame, neotame, herein the term “softener” designates an ingredient, which twinsweet, Saccharin and its salts, cyclamic acid and its salts, softens the gum base or chewing gum formulation and 65 glycyrrhizin, dihydrochalcones, thaumatin, monellin, Stevio encompasses waxes, fats, oils, emulsifiers, Surfactants and side and the like, alone or in combination. In order to provide solubilisers. longer lasting Sweetness and flavor perception, it may be US 8,603,440 B2 25 26 desirable to encapsulate or otherwise control the release of at Further chewing gum ingredients, which may be included least a portion of the artificial Sweetener. Techniques such as in the chewing gum according to the present invention, wet granulation, wax granulation, spray drying, spray chill include surfactants and/or solubilisers, especially when phar ing, fluid bed coating, coascervation, encapsulation in yeast maceutically or biologically active ingredients are present. As cells and fiber extrusion may be used to achieve the desired 5 examples of types of Surfactants to be used as solubilisers in release characteristics. Encapsulation of Sweetening agents a chewing gum composition according to embodiments of the can also be provided using another chewing gum component invention, reference is made to H. P. Fiedler, Lexikon der Such as a resinous compound. Hilfstoffe für Pharmacie, Kosmetik and Angrenzende Gebi Usage level of the high-intensity artificial sweetener will ete, pages 63-64 (1981) and the lists of approved food emul vary considerably and will depend on factors such as potency 10 sifiers of the individual countries. Anionic, cationic, ampho of the Sweetener, rate of release, desired sweetness of the teric or non-ionic solubilisers can be used. Suitable product, level and type of flavor used and cost considerations. solubilisers include lecithin, polyoxyethylene Stearate, poly Thus, the active level of high-potency artificial sweetener oxyethylene Sorbitan fatty acid esters, fatty acid salts, mono may vary from about 0 to about 8% by weight, preferably and diacetyl tartaric acid esters of mono and diglycerides of 0.001 to about 5% by weight. When carriers used for encap 15 edible fatty acids, citric acid esters of mono and diglycerides Sulation are included, the usage level of the encapsulated of edible fatty acids, saccharose esters of fatty acids, polyg sweetener will be proportionately higher. lycerol esters offatty acids, polyglycerol esters of interesteri If a low-calorie gum is desired, a low-caloric bulking agent fied castor oil acid (E476), sodium stearoylatylate, sodium can be used. Examples of low caloric bulking agents include lauryl Sulfate and Sorbitan esters of fatty acids and polyoxy polydextrose, Raftilose, Raftilin, fructooligosaccharides ethylated hydrogenated castor oil (e.g. the product sold under (NutraFlora.R.), palatinose oligosaccharides; guar gum the trade name CREMOPHOR), block copolymers of ethyl hydrolysates (e.g. Sun Fiber(R) or indigestible dextrins (e.g. ene oxide and propylene oxide (e.g. products sold under trade FibersolR). However, other low-calorie bulking agents can be names PLURONIC and POLOXAMER), polyoxyethylene used. fatty alcohol ethers, polyoxyethylene sorbitan fatty acid The chewing gum according to the present invention may 25 esters, Sorbitan esters offatty acids and polyoxyethylene ster contain aroma agents and flavoring agents including natural aric acid esters. and synthetic flavorings e.g. in the form of natural vegetable Particularly suitable solubilisers are polyoxyethylene components, essential oils, essences, extracts, powders, Stearates, such as for instance polyoxyethylene(8)Stearate including acids and other Substances capable of affecting the and polyoxyethylene(40)stearate, the polyoxyethylene sorbi taste profile. Examples of liquid and powdered flavorings 30 tan fatty acid esters sold under the trade name TWEEN, for include coconut, coffee, chocolate, Vanilla, grape fruit, instance TWEEN 20 (monolaurate), TWEEN 80 (mo orange, lime, menthol, liquorice, caramel aroma, honey nooleate), TWEEN 40 (monopalmitate), TWEEN 60 aroma, peanut, walnut, cashew, hazelnut, almonds, pine (monostearate) or TWEEN 65 (tristearate), mono and apple, Strawberry, raspberry, tropical fruits, cherries, cinna diacetyl tartaric acid esters of mono and diglycerides of mon, peppermint, wintergreen, spearmint, eucalyptus, and 35 edible fatty acids, citric acid esters of mono and diglycerides mint, fruit essence Such as from apple, pear, peach, Straw of edible fatty acids, sodium stearoylatylate, sodium lauryl berry, apricot, raspberry, cherry, pineapple, and plum Sulfate, polyoxyethylated hydrogenated castor oil, blockco essence. The essential oils include peppermint, spearmint, polymers of ethylene oxide and propyleneoxide and polyoxy menthol, eucalyptus, clove oil, bay oil, anise, thyme, cedar ethylene fatty alcohol ether. The solubiliser may either be a leaf oil, nutmeg, and oils of the fruits mentioned above. 40 single compound or a combination of several compounds. In The chewing gum flavor may be a natural flavoring agent, the presence of an active ingredient, the chewing gum may which is freeze-dried, preferably in the form of a powder, preferably also comprise a carrier known in the art. slices or pieces or combinations thereof. The particle size Active ingredients may advantageously be applied in a may be less than 3 mm, less than 2 mm or more preferred less chewing gum according to the invention. Active ingredients than 1 mm, calculated as the longest dimension of the particle. 45 generally refer to those ingredients that are included in a The natural flavoring agent may be in a form where the delivery system and/or compressible chewing gum composi particle size is from about 3 um to 2 mm, Such as from 4 um tion for the desired end benefit they provide to the user. In to 1 mm. Preferred natural flavoring agents include seeds Some embodiments, active ingredients can include medica from fruit e.g. from strawberry, blackberry and raspberry. ments, nutrients, nutraceuticals, herbals, nutritional Supple Various synthetic flavors, such as mixed fruit flavors may 50 ments, pharmaceuticals, drugs, and the like and combinations also be used in the present chewing gum centers. As indicated thereof. Moreover, in the present context, active ingredients above, the aroma agent may be used in quantities Smaller than may refer to flavor components, high intensity Sweeteners or those conventionally used. The aroma agents and/or flavors other taste establishing components. may be used in the amount from 0.01 to about 30% by weight Preferred API to be used in compressed chewing gum of the final product depending on the desired intensity of the 55 tablets according to embodiments of the invention are aroma and/or flavor used. Preferably, the content of aroma/ selected from the groups of antihistamines, anti-smoking flavor is in the range of 0.2 to 5%, more preferably 0.5 to 3%. agents, agents used for diabetes, decongestrants, peptides, by weight of the total composition. pain-relieving agents, antacids, nausea-relieving agents, sta In an embodiment of the invention, the flavoring agents tines, and other. comprise natural and synthetic flavorings in the form of natu 60 Most preferred API according to embodiments of the ral vegetable components, essential oils, essences, extracts, invention are cetirizine, levo cetirizine, nicotine, nicotine powders, including acids and other Substances capable of polacrilex, nicotine in combination with alkalineagents, met affecting the taste profile. formin, metformin HCL, phenylephrine, GLP-1, exenatide, In one embodiment of the invention, the flavor may be used MC-4 receptor antagonist, PPY(3-36), deca-peptide, KSL-W as taste masking in chewing gum comprising active ingredi 65 (acetate), fluor, and chlorhexidine. ents, which by themselves have undesired taste or which alter Also preferred API according to embodiments of the inven the taste of the formulation. tion are loratadine, des-loratadine, nicotine bitartrate, nico US 8,603,440 B2 27 28 tine in combination with caffeine, nicotine antagonists, com cylate, Mentol, Alkali metal alkyl sulphate, Sodium lauryl binations thereof or compounds comprising one or more of Sulphate, Glycerin, Bile acid, Lecithin, phosphatidylcholine, these, pseudoephedrine, flurbiprofen, paracetamol, acetyl phosphatidylserine, sphingomyelin, phophatidylethanola salicylic acid, Ibuprofen, antacida, cimetidine, ranitidine, mine, cephalin, lysolecithin, Hyaluronic acid: alkalimetal ondansetron, granisetron, metoclopramid, simvastatin, lovas salts, sodium, alkaline earth and aluminum, Octylphenoxy tatin, fluvastatin, acyclovir, benzydamin, rimonabant, Vareni polyethoxyethanol, Glycolic acid, Lactic acid, Chamomile cline, sildenafil, naltrexone, fluor in combination with fruit extract, Cucumber extract, Borage oil, Evening primrose oil, acids, derivatives, salts or isomers of chlorhexidine. Polyglycerin, Lysine, Polylysine, Triolein, Monoolein, Some groups of Suitable enhancers to e.g. enhance the Monooleates, Monolaurates, Polydocanol alkyl ethers, uptake of API include bile salts, cetomacrogols, chelating 10 Chenodeoxycholate, Deoxycholate, Glycocholic acid, Tau agents, citrates, cyclodextrins, detergents, enamine deriva rocholic acid, Glycodeoxycholic acid, Taurodeoxycholic tives, fatty acids, labrasol, lecithins, phospholipids, syntetic acid, Sodium glycocholate, Phosphatidylcholine, Phosphati and natural Surfactants, nonionic Surfactants, cell envelope dylserine, Sphingomyelin, Phosphatidylethanolamine, disordering compounds, solvents, steroidal detergents, chela Cephalin, Lysolecithin, Alkali metal hyaluronates, Chitosan, tors, solubilization agents, charge modifying agents, pH con 15 Poly-L-arginine, Alkyl glucoside, Saccharide alkyl ester, trol agents, degradative enzyme inhibitors, mucolytic or Fusidic acid derivatives, Sodium taurdihydrofusidate mucus clearing agents. (STDHF), L-O-phosphatidylcholine Didecanoyl (DDPC), Further groups of Suitable enhancers include modulatory Nitroglycerine, nitropruside, NCO5 3-(2-hydroxy-1-(me agents of epithelial junction physiology Such as nitric oxide thyl-ethyl)-2-nitrosohydrazino)-1-propanamine, NOC 12 (NO) stimulators, chitosan, and chitosan derivatives; and iV-ethyl-2-(1-ethyl-hydroxy-2-nitrosohydrazino)-etha vasodilator agents, selective transport-enhancing agents, sta namine, SNAP S-nitroso-N-acetyl-DL-penicillamine, bilizing delivery vehicles, carriers, Supports or complex NORI, NOR4, deacylmethylsulfoxide, azone, salicylamide, forming species with which exendins may be effectively com glyceryl-I.3-diacetoacetate, I.2-isopropylideneglycerine-3- bined, associated, contained, encapsulated or bound to acetoacetate), Amino acids, Amino acid salts, monoami stabilize an active agent for enhanced mucosal delivery; and 25 nocarboxlic acids, Glycine, alanine, phenylalanine, proline, membrane penetration-enhancing agents including Surfac hydroxyproline, hydroxyamino acids, serine, acidic amino tants, bile salts, phospholipid or fatty acid additives, mixed acids, aspartic acid, Glutamic acid, Basic amino acids, micelle, liposome, carrier, alcohol, enamine, NO donor com Lysine, N-acetylamino acids, N-acetylalanine, N-acetylphe pound, a long-chain amphipathic molecule, Small hydropho nylalanine, TM-acetylserine, N-acetylglycine, N-acetyl bic penetration enhancer, Sodium or a salicylic acid deriva 30 ysine, N-acetylglutamic acid, N-acetylproline, N-acetylhy tive, glycerol ester of acetoacetic acid, cyclodextrin or beta droxyproline, lactic acid, malic acid and citric acid and alkali cyclodextrin derivative, medium-chain fatty acid, chelating metal salts thereof, pyrrollidonecarboxylic acids, alkylpyr agent, amino acid or salt thereof, N-acetylamino acid or salt rolidonecarboxylic acid esters, N-alkylpyrrolidones, proline thereof, enzyme degradative to a selected membrane compo acyl esters, sodium lauryl phosphate, Sodium lauryl Sulphate, nent, inhibitor of fatty acid synthesis, inhibitor of cholesterol 35 Sodium oleyl phosphate, Sodium myristyl Sulphate, polyoxy synthesis, any combination of the membrane penetration ethylene alkyl ethers, polyoxyethylene alkyl esters, and cap enhancing agents. roic acid, alkylsaccharide, fusidic acid, polyethylene glycol, Examples of enhancers Suitable for application in com cetyl alcohol, polyvinylpyrolidone, Polyvinyl alcohol, Lano pressed chewing gum tablets according to embodiments of lin alcohol, Sorbitan monooleate, Ethylene glycol tetraacetic the invention include cetylpyridinium chloride (CPC), ben 40 acid, Bile acid conjugate with taurine, Cholanic acid and Zalkonium chloride, sodium lauryl sulfate, polysorbate 80, salts, Cyclodextran, Cyclodextrin, Cyclodextrin (beta), Polysorbate 20, cetyltrimethylammonium bromide, laureth9, Hydroxypropyl-f-cyclodetran, Sulfobutylether-f-cyclodex sodium salicylate, sodium EDTA, EDTA, aprotinin, sodium tran, Methyl-3-cyclodextrin, Chitosan glutamate, Chitosan taurocholate, saponins, bile salt derivatives, fatty acids, acetate, Chitosan hydrochloride, Chitosan hydrolactate, 1-O- Sucrose esters, aZone emulsion, dextran Sulphate, linoleic 45 alkyl-2-hydroxy-sn-glycero-3-phosphocholine, 3-O-alkyl-2- acid, labrafil, transcutol, urea, aZone, nonionic Surfactants, acetoyl-sn-glycero-1-phosphocholine, 1-O-alkyl-2-O- sulfoxides, sauric acid/PG, POE 23 lauryl ether, methoxysali acetyl-sn-glycero-3-phospho(N.N.N-trimethyl)hexanol cylate, dextran Sulfate, methanol, ethanol, Sodium cholate, amine, propylene glycol, tetradecylmaltoside (TDM), Sodium taurocholate, Lysophosphatidylcholine, Alkylglyco Sucrose dedecanoate. sides, polysorbates, Sorbitan esters, Poloxamer block copoly 50 Examples of Suitable mucoadhesives as enhancers accord mers, PEG-35 castor oil, PEG-40 hydrogenated castor oil, ing to embodiments of the invention include Carbopol 934+ Caprocaproyl macrogol-8 glycerides, PEG-8 caprylic/capric, HPC, Maize--Carbopol 907, HPC (hydroxypropyl cellulose), glycerides, Dioctylsulfosuccinate, Polyethylene lauryl ether, Na-CMC, HPMC (hydroxypropylmethylcellulose), HEMA Ethoxydiglycol, Propylene glycol, mono-di-caprylate, Glyc hydroxyethyl metacrylate, Carbopol 907 crosslinked with erol monocaprylate, Glyceryl fatty acids (C. sub.8-C. Sub.18) 55 sucrose, Polyacrylic acids (PAA), Chitosans, Lectins, Poly ethoxylated. metacrylate derivatives, Hyaluronic acid, P(AA-co-PEG) Oleic acid, Linoleic acid, Glyceryl caprylate/caprate, monomethylether monomethacrylate, PAA-PVP (Poly Glyceryl monooleate, Glyceryl monolaurate, Capryliccapric acrylic acid-poly vinyl pyrrilidone), PVP-PEG, methylcellu triglycerides, Ethoxylated nonylphenols, PEG-(8-50) stear lose, N-Trimethyl Chitosans, PDMAEMA, poly(dimethyl ates, Olive oil PEG-6, esters, Triolein PEG-6 esters, Lecithin, 60 aminoethyl methacrylate), HEC Hydroxethyl Cellulose, Car d-alpha tocopherol polyethylene glycol 1,000 succinate, Cit bomer 940, Carbomer 971, Polyethylene Oxide, Dextrin, ric acid, Sodium citrate, BRIJ, Sodium laurate, 5-methox Poly(Methyl Vinyl Ether/Maleic Anhydride), Polycarbophil ysalicylic acid, Bile salts, Acetyl salicylate. ZOT, Docosa that is polymers of acrylic acid crosslinked with divinylgly hexaenoic acid, Alkylglycosides, Sodium glycocholate (GC col, PVP (PVP: Poly vinyl pyrrilidone), Agar, Tragacanth, Na), Sodium taurocholate (TC-Na), EDTA, Choline 65 Sodium Alginate, Karaya gum, MEC, HPC(HPC: salicylate, Sodium caprate (Cap-Na), N-lauryl-beta-D-mal Hydroxy propyl cellulose), Lectins, AB Block copolymer of topyranoside (LM), Diethyl maleate, Labrasol, Sodium sali oligo (methyl methacrylate) and PAA, Polymers with thiol US 8,603,440 B2 29 30 groups, Spheromers, Thiomers, Alginic acid sodium salt, The first level of the ATC is split into 14 main groups based Carbopol 974P (Carbomer), EC (EC: Etylcellulose), CMC on the anatomical group: (CMC: Carboxymethyl cellulose), Dextran, Guar Gum, Pec A: Alimentary tract and metabolism tins, Starch, Gelatin, Casein, Acrylic acid polymers, Poly B: Blood and blood forming organs mers of acrylic acid esters, Acrylic acid copolymers, Vinyl C: Cardiovascular system polymers, Vinyl copolymers, Polymers of Vinyl alcohols, D: Dermatologicals Alcoxy polymers, polyethylene oxide polymers, and poly G: Genito urinary system and sex hormones ethers. H: Systemic hormonal preparations, excl. sex hormones and Some groups of Suitable enhancers include solubilization insulins 10 J: Antiinfectives for systemic use agents; charge modifying agents; pH control agents; degra L: Antineoplastic and immunomodulating agents dative enzyme inhibitors; modulatory agents of epithelial M: Musculo-skeletal system junction physiology, such as nitric oxide (NO) stimulators, N: Nervous system chitosan, orchitosan derivatives; vasodilator agents; selective P: Antiparasitic products, insecticides and repellents transport-enhancing agents; stabilizing delivery vehicles, 15 R: Respiratory system carriers, Supports or complex-forming species with which S: Sensory organs exendin(s) is/are effectively combined, associated, con V: Various tained, encapsulated or bound to stabilize the active agent for Further subdivision is done into a second, third, fourth and enhanced mucosal delivery; Small hydrophilic penetration fifth sub-group, which is based on the therapeutic main group, enhancers; emulsifiers, mucolytic or mucus clearing agents; the therapeutic/pharmacological Subgroup, the chemical/ membrane penetration-enhancing agents such as e.g., (i) a therapeutic/pharmacological Subgroup, and the chemical Surfactant, (ii) a bile salt, (iii) a phospholipid or fatty acid Substance subgroup respectively. In this sense each active additive, mixed micelle, liposome, or carrier, (iv) an alcohol, ingredient has been given a unique ATC identification code (v) an enamine, (iv) an NO donor compound, (vii) a long indicating where the active ingredient may be useful. chain amphipathic molecule, (viii) a small hydrophobic pen 25 However, as some active ingredients are useful in more etration enhancer, (ix) Sodium or a salicylic acid derivative, than one area, some of the active ingredients mentioned in this (X) a glycerol ester of acetoacetic acid, (xi) a cyclodextrin or document belong to two or more of the mentioned groups, beta-cyclodextrin derivative, (xii) a medium-chain fatty acid, e.g. phenylephrine, which has an ATC identification code in (xiii) a chelating agent, (xiv) an amino acid or salt thereof, both C, R, and S, i.e. both CO1CA06, R01 AA04, R01 AB01, (XV) an N-acetylamino acid or salt thereof (Xvi) an enzyme 30 R01 BAO3, S01FB01, and S01GA05 are ATC identification degradative to a selected membrane component, (Xvii) an codes identifying phenylephrine. inhibitor offatty acid synthesis, (xviii) an inhibitor of choles The following list discloses examples of active ingredients terol synthesis; or (xiv) any combination of the membrane which can be classified according to the ATC classification penetration enhancing agents of (i)-(Xviii)). mentioned above and which are active ingredients which may In various embodiments of the invention, exendin is com 35 be used in a compressed chewing gum according to embodi bined with one, two, three, four or more of the mucosal ments of the invention: delivery-enhancing agents recited above. Ephedrine, Magaldrate, Pseudoephedrine, Sildenafil. Some Suitable enhancers for application according to the Xylocalne, Benzalconium chloride, Caffeine, Phenylephrine, present invention include pH control agents selected from the Amfepramone, Orlistat, Sibutramine, Acetaminophen, Aspi group consisting of Acetic acid, Adipic acid, Citric acid, 40 rin, Aluminum amino acetate, Aluminum amino acetate in Fumaric acid, Glucono-6-lactone, Gluconic acid, Lactic acid, combination with Magnesium oxide, Aluminum oxide Malic acid, Maleic acid, Tartaric acid, Succinic acid, Propi hydrate in combination with Magnesiumoxide, Calcium car onic acid, Ascorbic acid, Phosphoric acid, Sodium ortho bonate in combination with Magnesium hydroxide, Calcium phosphate, Potassium orthophosphate, Calcium orthophos carbonate, Dihydroxy Aluminum Sodium carbonate, Magne phate, Sodium diphosphate, Potassium diphosphate, Calcium 45 sium oxide, Glitazones, Metformin, Chlorpromazine, diphosphate, Pentasodium triphosphate, Pentapotassium Dimenhydrinat, Domperidone, Meclozine, Metoclopramide, triphosphate, Sodium polyphosphate, Potassium polyphos Odansetron, Prednisolone, Promethazine, Acrivastine, Ceti phate, Carbonic acid, Sodium carbonate, Sodium bicarbon rizine, Cinnarizine, Clemastine, Cyclizine, Desloratadine, ate, Potassium carbonate, Calcium carbonate, Magnesium Dexchlorpheniramine, Dimenhydrinate, Ebastine, Fexofena carbonate, Magnesium oxide, or any combination thereof. 50 dine, Ibuprofen, Levolevoproricin, Loratadine, Meclozine, The Suitable pH control agents suitable according to the Mizolastine, Promethazine, Miconazole, Vitamin B12, Folic present invention include buffers. acid, Ferro compounds, vitamin C, Chlorhexidine diacetate, Examples of dry binders to be used according to embodi Fluoride, Decapeptide KSL, Aluminum fluoride, Aminoch ments of the invention include mikro-crystalline cellulose elated calcium, Ammonium fluoride, Ammonium fluorosili (MCC), silicified micro-crystalline cellulose (SMCC), spray 55 cate, Ammonium monofluorphosphate, Calcium fluoride, dried lactose, fast flow lactose, anhydrous lactose, Sucrose, Calcium gluconate, Calcium glycerophosphate, Calcium lac mannitol, mannitol EZ. dextrose, fructose, Sorbitol, povi tate, Calcium monofluorphosphate, Calciumcarbonate, Car done, copovidone, dicalcium phosphate (DCP), starch (corn, bamide, Cetyl pyridinium chloride, Chlorhexidine, Chlo potato and rice), pre-gelatinized starch, or combinations rhexidine digluconate, Chlorhexidine Chloride, thereof. A number offiller materials may furthermore be used 60 Chlorhexidine diacetate, CPP Caseine Phospho Peptide, as dry binders. Hexetedline, Octadecentyl Ammonium fluoride, Potasium Active ingredients may be classified according to The Ana fluorosilicate, Potassium Chloride, Potassium monofluor tomical Therapeutic Chemical (ATC) classification system, phosphate, Sodium bicarbonate, Sodium carbonate, Sodium which is a system for classification of medicinal products fluoride, Sodium fluorosilicate, Sodium monofluorphos according to their primary constituent and to the organ or 65 phate, Sodium tripolyphosphate, Stannous fluoride, Stearyl system on which they act and their chemical, pharmacologi Trihydroxyethyl Propylenediamine Dihydrofluoride, Stron cal and therapeutic properties. tium chloride, Tetra potassium pyrophosphate, Tetra sodium US 8,603,440 B2 31 32 pyrophosphate, Tripotassium orthophosphate, Trisodium Anti-arrytmic, Appetite Suppressant, Antifungal, Anti-in orthophosphate, Alginic acid, Aluminum hydroxide, Sodium flammatory, Broncho dilator, Cardiovascular drugs, Coro bicarbonate, Sildenafil, Tadalafil. Vardenafil, Yohimbine, nary dilator, Cerebral dilator, Peripheral vasodilator, Anti Cimetidine, Nizatidine, Ranitidine, Acetylsalicylic acid, Clo infective, Psychotropic, Anti-manic, Stimulant, pidogrel, Acetylcysteine, Bromhexine, Codeine, Dex Antihistamine, Laxative, Decongestrant, Gastro-intestinal tromethorphan, Diphenhydramine, Noscapine, Phenylpro sedative, Sexual dysfunction agent, Desinfectants, Anti-diar panolamine, Vitamin D. Simvastatin, Bisacodyl, Lactitol, rheal, Anti-anginal Substance, Vasodilator, Anti-hypertensive Lactulose, Magnesium oxide, Sodium picosulfate, Senna agent, Vasoconstrictor, Migraine treating agent, Antibiotic, glycosides, Benzocaine, Lidocaine, Tetracaine, Almotriptan, Tranquilizer, Ntipsychotic, Anti-tumor drug, Anticoagulant, Eletriptan, Naratriptan, Rizatriptan, Sumatriptan, Zolmitrip 10 Antithrombotic agent, Hypnotic, Sedative, Anti-emetic, tan, Calcium, Chromium, Copper, Iodine, Iron, Magnesium, Anti-, auseant, Anticonvulsant, Neuromuscular agent, Hyper Manganese, Molybdenium, Phosphor, Selenium, Zinc, Nico and hypoglycaemic, Thyroid and antithyroid, Diuretic, Anti tine, Nicotine bitaritrate, Nicotine pftalate, Nicotine polac spasmodic, Uterine relaxant, Anti-obesity agent, Anoretic, rilex, Nicotine sulphate, Nicotine tartrate, Nicotine citrate, Spasmolytics, Anabolic agent, Erythropoietic agent, Anti Nicotine lactate, Chloramine, Hydrogenperoxide, Metron 15 asthmatic, Expectorant, Cough Suppressant, Mucolytic, Anti idazole, Triamcinolonacetonide, Benzethonium Chl., Cetyl uricemic agent, Dental vehicle, Breath freshener, Antacid, pyrid. Chl. Chlorhexidine, Fluoride, Lidocaine, Amphoteri Anti-diuretc., Anti-flatulent, Betablokker, Teeth Whitener, cin, Miconazole, Nystatin, Fish oil, Ginkgo Biloba, Ginseng, Enzyme, Co-enzyme, Protein, Energy booster, Fiber, Probi Ginger, Purple coneflower, Saw Palmetto, Cetirizine, Levo otics, Prebiotics, Antimicrobial agent, NSAID, Anti-tussives, cetirizine, Loratadine, Diclofenac, Flurbiprofen, Acrivastine Decongestrants, Anti-histamines, Expectorants, Anti-diar Pseudoephedrine, Loratadine Pseudoephedrine, Glu rheals, Hydrogen antagonists, Proton pump inhibitors, Gen cosamine, hyaluronic acid, Decapeptide KSL-W. Decapep eral nonselective CNS depressants, General nonselective tide KSL, Resveratrol, Misoprostol, Bupropion, Nicotine, CNS stimulants, Selectively CNS function modifying drugs, Ondansetron HCl, Esomeprazole, Lansoprazole, Omepra Antiparkinsonism, Narcotic-analgetics, Analgetic-antipyret Zole, Pantoprazole, Rabeprazole, Bacteria and the like, Lop 25 ics, Psychopharmacological drugs, and Sexual dysfunction eramide, Simethicone, Acetylsalicylic acid and others, agents. Sucralfate, VitaminA, Vitamin B1, Vitamin B12, Vitamin B2, Examples of useful active ingredients include: Casein Vitamin B6, Biotin, Vitamin C, Vitamin D. Vitamin E, Folinic glyco-macro-peptide (CGMP), Nicotine, Nicotine bitartrate, acid, Vitamin K, Niacin, Q10, Clotrimazole, Fluconazole, Nicotine sulphate, Nicotine tartrate, Nicotine pfalate, Nico Itraconazole, Ketoconazole, Terbinafine, Allopurinol, 30 tine lactate, Nicotinecitrate, Nicotine polacrilex, Triclosan, Probenecid, Atorvastatin, Fluvastatin, Lovastatin, Nicotinic Cetyl pyridinium chloride, Domiphen bromide, Quarternary acid, Pravastatin, Rosuvastatin, Simvastatin, Pilocarpine, ammonium salts, Zinc components, Sanguinarine, Fluorides, Naproxen, Alendronate, Etidronate, Raloxifene, Risedronate, Alexidine, Octonidine, EDTA, Aspirin, Acetaminophen, Ibu Benzodiazepines, Disulfuram, Naltrexone, Buprenorphine, profen, Ketoprofen, Diflunisal, Fenoprofen calcium, Codeine, Dextropropoxyphene, Fentanyl, Hydromorphone, 35 Naproxen, Tolimetin Sodium, Indomethacin, BenZonatate, Ketobemidone, Ketoprofen, Methadone, Morphine, Caramiphen edisylate, Menthol, Dextromethorphan hydro Naproxen, Nicomorphine, Oxycodone, Pethidine, Tramadol, bromide, Theobromine hydrochloride, Chlophendianol Amoxicillin, Ampicillin, Azithromycin, Ciprofloxacin, Hydrochloride, Pseudoephedrine Hydrochloride, Phenyleph Clarithromycin, Doxycyclin, Erythromycin, Fusidic acid, rine, Phenylpropanolamine, Pseudoephedrine sulphate, Bro Lymecycline, Metronidazole, Moxifloxacin, Ofloxacin, 40 mpheniramine maleate, Chlorpheniramine-maleate, Carbi Oxytetracycline, Phenoxymethylpenicillin, Rifamycins, noxamine maleate, Clemastine fumarate, Roxithromycin, Sulfamethizole, Tetracycline, Trimethoprim, Dexchlorpheniramine maleate, Dephenhydramine hydro Vancomycin, Acarbose, Glibenclamide, Gliclazide, Glime chloride, Diphenpyralide hydrochloride, AZatadine maleate, piride, Glipizide, Insulin, Repaglinide, Tolbutamide, Oselta Diphenhydramine citrate, Doxylamine Succinate, Promet mivir, Aciclovir, Famciclovir, Penciclovir, Valganciclovir, 45 hazine hydrochloride, Pyrilamine maleate, Tripellenamine Amlopidine, Diltiazem, Felodipine, Nifedipine, Verapamil, citrate, Triprolidine hydrochloride, Acrivastine, Loratadine, Finasteride, Minoxidil, Cocaine, Buphrenorphin, Clonidine, Brompheniramine, Dexbrompheniamine, Guaifenesin, Methadone, Naltrexone, Calciumantagonists, Clonidine, Ipecac, Potassium iodide, Terpin hydrate, Loperamide, Ergotamine, B-blockers, Aceclofenac, Celecoxib, Dexipro Famotidine, Ranitidine, Omeprazole, Lansoprazole, Ali fen, Etodolac, Indometacin, Ketoprofen, Ketorolac, Lornoxi 50 phatic alcohols, Barbiturates, Caffeine, Nicotine, Strychnine, cam, Meloxicam, Nabumetone, Oiroxicam, Parecoxib, Phe Picrotoxin, Pentyenetetrazol, Phenyhydantoin, Phenobar nylbutaZone, Piroxicam, Tiaprofenic acid, Tolfenamic acid, bital, Primidone, Carbamazapine, EtoxSuximide, MethSux Aripiprazole, Chlorpromazine, Chlorprothixene, Clozapine, imide, Phensuximide, Trimethadione, Diazepam, Benzodiaz Flupentixol, Fluphenazine, Haloperidol, Lithium carbonate, epines, Phenacemide, Pheneturide, Acetazolamide, Lithium citrate, Melperone, Penfluridol, Periciazine, Per 55 Sulthiame, Bromide, Levodopa, Amantadine, Morphine, phenazine, Pimozide, Pipamperone, Prochlorperazine, Ris Heroin, Hydromorphone, Metopon, Oxymorphone, peridone. Thioridizin, Fluconazole, Itraconazole, Ketocona Levophanol, Codeine, Hydrocodone, Xycodone, Nalorphine, Zole, Voriconazole, Opium, BenZodiazepines, Hydroxine, Naloxone, Naltrexone, Salicylates, Phenylbutazone, Meprobamate, Phenothiazine, Aluminumaminoacetate, Indomethacin, Phenacetin, Chlorpromazine, Methotrimepra Esomeprazole, Famotidine, Magnesium oxide, Nizatide, 60 Zine, Haloperidol, Clozapine, Reserpine, Imipramine, Tra Omeprazole, Pantoprazole, Fluconazole, Itraconazole, Keto nylcypromine, Phenelzine, Lithium, Sildenafil citrate, Tad conazole, Metronidazole, Amphetamine, Atenolol, Biso alafil, and Vardenafil CL. prolol fumarate, Metoprolol, Metropolol, Pindolol, Propra Examples of useful active ingredients include active ingre nolol, Auranofin, and BendaZac. dients selected from the groups of ace-inhibitors, antianginal Further examples of useful active ingredients include 65 drugs, anti-arrhythmias, anti-asthmatics, anti-cholesterolem active ingredients selected from the therapeutical groups ics, analgesics, anesthetics, anticonvulsants, anti-depres comprising: Analgesic, Anaestetic, Antipyretic, Antiallergic, sants, anti-diabetic agents, anti-diarrhea preparations, anti US 8,603,440 B2 33 34 dotes, anti-histamines, anti-hypertensive drugs, anti Active antacid ingredients can include, but are not limited inflammatory agents, anti-lipid agents, anti-manics, anti to, the following: aluminum hydroxide, dihydroxyaluminum nauseants, anti-stroke agents, anti-thyroid preparations, anti aminoacetate, aminoacetic acid, aluminum phosphate, dihy tumor drugs, anti-viral agents, acne drugs, alkaloids, amino droxyaluminum sodium carbonate, bicarbonate, bismuthalu acid preparations, anti-tussives, anti-uricemic drugs, anti-vi minate, bismuth carbonate, bismuth Subcarbonate, bismuth ral drugs, anabolic preparations, systemic and non-systemic Subgallate, bismuth Subnitrate, bismuth Subsilysilate, cal anti-infective agents, anti-neoplasties, antiparkinsonian cium carbonate, calcium phosphate, citrate ion (acid or salt), agents, anti-rheumatic agents, appetite stimulants, biological amino acetic acid, hydrate magnesium aluminate Sulfate, response modifiers, blood modifiers, bone metabolism regu magaldrate, magnesium aluminosilicate, magnesium carbon 10 ate, magnesium glycinate, magnesium hydroxide, magne lators, cardiovascular agents, central nervous system stimu sium oxide, magnesium trisilicate, milk solids, aluminum lates, cholinesterase inhibitors, contraceptives, deconges mono-ordibasic calcium phosphate, tricalcium phosphate, tants, dietary Supplements, dopamine receptor agonists, potassium bicarbonate, Sodium tartrate, Sodium bicarbonate, endometriosis management agents, enzymes, erectile dys magnesium aluminosilicates, tartaric acids and salts. A vari function therapies Such as sildenafil citrate, which is currently 15 ety of nutritional Supplements may also be used as active marketed as Viagra TM, fertility agents, gastrointestinal agents, ingredients including virtually any vitamin or mineral. For homeopathic remedies, hormones, hypercalcemia and example, vitaminA, Vitamin C, Vitamin D. Vitamin E. Vitamin hypocalcemia management agents, immunomodulators, K, vitamin B6, vitamin B12, thiamine, riboflavin, biotin, folic immunosuppressives, migraine preparations, motion sick acid, niacin, pantothenic acid, Sodium, potassium, calcium, ness treatments, muscle relaxants, obesity management magnesium, phosphorus, Sulfur, chlorine, iron, copper, agents, osteoporosis preparations, oxytocics, parasym iodine, Zinc, Selenium, manganese, choline, chromium, patholytics, parasympathomimetics, prostaglandins, psycho molybdenum, fluorine, cobalt and combinations thereof, may therapeutic agents, respiratory agents, sedatives, Smoking be used. Examples of nutritional Supplements that can be used cessation aids such as bromocriptine or nicotine, sym as active ingredients are set forth in U.S. Patent Application patholytics, tremor preparations, urinary tract agents, vasodi 25 Publication Nos. 2003/0157213 AI, 2003/0206993 and 2003/ lators, laxatives, antacids, ion exchange resins, anti-pyretics, 0099741 AI which are incorporated in their entirety herein by appetite Suppressants, expectorants, anti-anxiety agents, anti reference for all purposes. Various herbals may also be used ulcer agents, anti-inflammatory Substances, coronary dila as active ingredients such as those with various medicinal or tors, cerebral dilators, peripheral vasodilators, psycho-trop dietary Supplement properties. Herbals are generally aro ics, stimulants, anti-hypertensive drugs, vasoconstrictors, 30 matic plants or plant parts and or extracts thereofthat can be migraine treatments, antibiotics, tranquilizers, anti-psychot used medicinally or for flavoring. Suitable herbals can be ics, anti-tumor drugs, anti-coagulants, anti-thrombotic drugs, used singly or in various mixtures. Commonly used herbs hypnotics, anti-emetics, anti-nauseants, anti-convulsants, include Echinacea, Goldenseal, Calendula, Rosemary, neuromuscular drugs, hyper- and hypo-glycemic agents, thy Thyme, Kava Kava, Aloe, Blood Root, Grapefruit Seed roid and anti-thyroid preparations, diuretics, anti-spasmod 35 Extract, Black Cohosh, Ginseng, Guarana, Cranberry, Ginko ics, terine relaxants, anti-obesity drugs, erythropoietic drugs, Biloba, St. John's Wort, Evening Primrose Oil, Yohimbe anti-asthmatics, cough Suppressants, mucolytics, DNA and Bark, Green Tea, Ma Huang, Maca, Bilberry, Lutein, and genetic modifying drugs, and combinations thereof. combinations thereof. Examples of active ingredients contemplated for use in the Especially when hydrophilic, encapsulation of the active present invention can include antacids, H2-antagonists, and 40 ingredient will result in a delay in the release of the predomi analgesics. For example, antacid dosages can be prepared nant amount of the active ingredient during consumption of a using the ingredients calcium carbonate alone or in combina compressible chewing gum that includes the encapsulated tion with magnesium hydroxide, and/or aluminum hydrox active ingredient (e.g., as part of a delivery system added as an ide. Moreover, antacids can be used in combination with ingredient to the compressible chewing gum), in some H2-antagonists. 45 embodiments, the release profile of the ingredient (e.g., the Analgesics include opiates and opiate derivatives, such as active ingredient) can be managed for a compressiblegum by OxycontinTM, ibuprofen, aspirin, acetaminophen, and combi managing various characteristics of the ingredient, delivery nations thereof that may optionally include caffeine. system containing the ingredient, and/or the compressible Other drug active ingredients for use in embodiments can chewing gum containing the delivery system and/or how the include anti-diarrheals such as ImmodiumTMAD, anti-hista 50 delivery system is made. For example, characteristics may mines, anti-tussives, decongestants, vitamins, and breath include one or more of the following: tensile strength of the fresheners. Also contemplated for use herein are anxiolytics delivery system, water solubility of the ingredient, water such as XanaxTM; anti-psychotics such as ClozariltM and solubility of the encapsulating material, water solubility of HaldolTM; non-steroidal anti-inflammatories (NSAIDs) such the delivery system, ratio of ingredient to encapsulating mate as ibuprofen, naproxen sodium, VoltarenTM and LodineTM, 55 rial in the delivery system, average or maximum particle size anti-histamines such as ClaritinTM HismanalTM, RelafenTM, of ingredient, average or maximum particle size of ground and TavistTM; antiemetics such as KytrilTM and CesametTM: delivery system, the amount of the ingredient or the delivery bronchodilators such as BentolinTM, Proventil TM, anti-de system in the compressible chewing gum, ratio of different pressants such as ProzacTM, ZoloftTM, and PaxilTM; anti-mi polymers used to encapsulate one or more ingredients, hydro graines such as ImigratM, ACE-inhibitors such as VasotecTM, 60 phobicity of one or more polymers used to encapsulate one or CapotenTM and Zestrilt M. anti-Alzheimer's agents, such as more ingredients, hydrophobicity of the delivery system, the NicergolineTM, and Cah-antagonists such as ProcardiaTM, type or amount of coating on the delivery system, the type or Adalat TM, and CalanTM. amount of coating on an ingredient prior to the ingredient The popular H2-antagonists which are contemplated for being encapsulated, etc. use in the present invention include cimetidine, ranitidine 65 In some embodiments, the release profiles of one or more hydrochloride, famotidine, nizatidien, ebrotidine, mifenti components of an effervescing system are managed for a dine, roXatidine, pisatidine and aceroxatidine. compressible gum. The effervescent system may include one US 8,603,440 B2 35 36 or more edible acids and one or more edible alkaline materi Typically, encapsulation of the appetite Suppressor will als. The edible acid(s) and the edible alkaline material(s) may result in a delay in the release of the predominant amount of react together to generate effervescence. In some embodi the appetite Suppressor during consumption of a compress ments, the alkaline material(s) may be selected from, but is ible chewing gum that includes the encapsulated appetite not limited to, alkali metal carbonates, alkali metal bicarbon Suppressor (e.g., as part of a delivery system added as an ates, alkaline earth metal carbonates, alkaline earth metal ingredient to the compressible chewing gum). In some bicarbonates, and combinations thereof. The edible acid(s) embodiments, the release profile of the ingredient (e.g., the may be selected from, but is not limited to, citric acid, phos appetite Suppressor) can be managed for a compressible gum phoric acid, tartaric acid, malic acid, ascorbic acid, and com by managing various characteristics of the ingredient, deliv 10 ery system containing the ingredient, and/or the compressible binations thereof. In some embodiments, an effervescing sys chewing gum containing the delivery system and/or how the tem may include one or more other ingredients such as, for delivery system is made. For example, characteristics may example, carbon dioxide, oral care ingredients, flavorants, include one or more of the following: tensile strength of the etc. delivery system, water solubility of the ingredient, water For examples of use of an effervescing system in a chewing 15 solubility of the encapsulating material, water solubility of gum, refer to U.S. Provisional Patent No. 60/618,222 filed the delivery system, ratio of ingredient to encapsulating mate Oct. 13, 2004, and entitled “Effervescent Pressed Gum Tablet rial in the delivery system, average or maximum particle size Compositions, the contents of which are incorporated herein of ingredient, average or maximum particle size of ground by reference for all purposes. Other examples can be found in delivery system, the amount of the ingredient or the delivery U.S. Pat. No. 6,235,318, the contents of which are incorpo system in the compressible chewing gum, ratio of different rated herein by reference for all purposes. Typically, encap polymers used to encapsulate one or more ingredients, hydro Sulation of the one or more ingredients in an effervescing phobicity of one or more polymers used to encapsulate one or system will result in a delay in the release of the predominant more ingredients, hydrophobicity of the delivery system, the amount of the one or more ingredients during consumption of type or amount of coating on the delivery system, the type or a compressible chewing gum that includes the encapsulated 25 amount of coating on an ingredient prior to the ingredient one or more ingredients (e.g., as part of a delivery system being encapsulated, etc. added as an ingredient to the compressible chewing gum In some embodiments, the release profiles of one or more composition). The release profile of the one or more ingredi breath fresheners are managed for a compressible gum. ents can be managed for a compressible gum by managing Breath fresheners can include essential oils as well as various various characteristics of the ingredient, delivery system con 30 aldehydes, alcohols, and similar materials. In some embodi taining the ingredient, and/or the compressible chewing gum ments, essential oils can include oils of spearmint, pepper containing the delivery system and/or how the delivery sys mint, wintergreen, Sassafras, chlorophyll, citral, geraniol, tem is made. For example, characteristics may include one or cardamom, clove, sage, carvacrol, eucalyptus, cardamom, more of the following: tensile strength of the delivery system, magnolia bark extract, marjoram, cinnamon, lemon, lime, water solubility of the ingredient, water solubility of the 35 grapefruit, and orange. In some embodiments, aldehydes encapsulating material, water solubility of the delivery sys Such as cinnamic aldehyde and salicylaldehyde can be used. tem, ratio of ingredient to encapsulating material in the deliv Additionally, chemicals such as menthol, carvone, iso-garri ery system, average or maximum particle size of ingredient, gol, and anethole can function as breath fresheners. Of these, average or maximum particle size of ground delivery system, the most commonly employed are oils of peppermint, spear the amount of the ingredient or the delivery system in the 40 mint and chlorophyll. compressible chewing gum, ratio of different polymers used In addition to essential oils and chemicals derived from to encapsulate one or more ingredients, hydrophobicity of them, in Some embodiments, breath fresheners can include one or more polymers used to encapsulate one or more ingre but are not limited to Zinc citrate, Zinc acetate, Zinc fluoride, dients, hydrophobicity of the delivery system, the type or Zinc ammonium Sulfate, Zinc bromide, Zinc iodide, Zinc chlo amount of coating on the delivery system, the type or amount 45 ride, Zinc nitrate, Zinc fluorosilicate, Zinc gluconate, Zinc of coating on an ingredient prior to the ingredient being tartarate, Zinc succinate, Zinc formate, Zinc chromate, Zinc encapsulated, etc. phenol Sulfonate, Zinc dithionate, Zinc sulfate, silver nitrate, In some embodiments, the release profiles of one or more Zinc salicylate, Zinc glycerophosphate, copper nitrate, chlo appetite Suppressors are managed for a compressible gum. rophyll, copper chlorophyll, chlorophyllin, hydrogenated Appetite Suppressors can be ingredients such as fiber and 50 cottonseed oil, chlorine dioxide, beta cyclodextrin, Zeolite, protein that function to depress the desire to consume food. silica-based materials, carbon-based materials, enzymes Such Appetite Suppressors can also include benzphetamine, dieth as laccase, and combinations thereof. In some embodiments, ylpropion, mazindol, phendimetrazine, phentermine, hoodia the release profiles of probiotics can be managed for a com (P57), OlibraTM, ephedra, caffeine and combinations thereof. pressiblegum including, but not limited to lactic acid produc Appetite Suppressors are also known by the following trade 55 ing microorganisms such as Bacillus coagulans, Bacillus names: AdipexTM, AdipostTM, BontrilTM PDM, BontrilTM subtilis, Bacillus laterosporus, Bacillus laevolacticus, Sporo Slow Release, DidrexTM, FastinTM, IonaminTM, Mazanor TM, lactobacillus inulinus, Lactobacillus acidophilus, Lactoba Melfiat TM, ObenixTM, PhendietTM, Phendiet-105TM, Phenter cillus curvatus, Lactobacillus plantarum, Lactobacillus jens cott M, PhentrideTM, PlegineTM, Prelu-2TM, Pro-FastTM, PT eni, Lactobacillus casei, Lactobacillus fermentum, 105STM, SanorexTM, TenuateTM, SanorexTM, TenuateTM, 60 Lactococcus lactis, Pedioccocus acidilacti, Pedioccocus pen Tenuate DospanTM, Tepanil Ten-TabtM, TeramineTM, and tosaceus, Pedioccocus urinae, Leuconostoc mesenteroides, ZantryITM. These and other suitable appetite suppressors are Bacillus coagulans, Bacillus subtilis, Bacillus laterosporus, further described in the following U.S. patents, all of which Bacillus laevolacticus, Sporolactobacillus inulinus and mix are incorporated in their entirety by reference hereto: U.S. tures thereof. Breath fresheners are also known by the follow Pat. No. 6,838,431 to Portman, U.S. Pat. No. 6,716,815 to 65 ing trade names: RetsynTM, ActizolTM, and NutrazinTM. Portman, U.S. Pat. No. 6,558,690 to Portman, U.S. Pat. No. Examples of malodor-controlling compositions are also 6,468,962 to Portman, U.S. Pat. No. 6,436,899 to Portman. included in U.S. Pat. No. 5,300,305 to Stapler et al. and in US 8,603,440 B2 37 38 U.S. Patent Application Publication Nos. 2003/0215417 and sition detersive and foaming properties. Suitable examples of 2004/0081713 which are incorporated in their entirety herein surfactants are water-soluble salts of higher fatty acid by reference for all purposes. monoglyceride monosulfates, such as the Sodium salt of the Typically, encapsulation of the breath-freshening ingredi monosulfated monoglyceride of hydgrogenated coconut oil ent will result in a delay in the release of the predominant fatty acids, higher alkylsulfates such as sodium lauryl Sulfate, amount of the active ingredient during consumption of a alkyl aryl Sulfonates such as sodium dodecyl benzene Sul compressible chewing gum that includes the encapsulated fonate, higher alkylsulfoacetates, sodium lauryl Sulfoacetate, breath-freshening ingredient (e.g., as part of a delivery sys higher fatty acid esters of 1,2-dihydroxy propane Sulfonate, tem added as an ingredient to the compressible chewing gum and the Substantially Saturated higheraliphatic acylamides of composition). In some embodiments, the release profile of the 10 lower aliphatic amino carboxylic acid compounds, Such as ingredient (e.g., the breath-freshening ingredient) can be those having 12 to 16 carbons in the fatty acid, alkyl or acyl managed for a compressible gum by managing various char radicals, and the like. Examples of the last mentioned amides acteristics of the ingredient, delivery system containing the are N-lauroyl sarcosine, and the Sodium, potassium, and etha ingredient, and/or the compressible chewing gum containing nolamine salts of N-lauroyl, N-myristoyl, or N-palmitoylsar the delivery system and/or how the delivery system is made. 15 cosine. In addition to surfactants, dental care ingredients can For example, characteristics may include one or more of the include antibacterial agents such as, but not limited to, tri following: tensile strength of the delivery system, water solu closan, chlorhexidine, Zinc citrate, silver nitrate, copper, bility of the ingredient, water solubility of the encapsulating limonene, and cetyl pyridinium chloride. In some embodi material, water solubility of the delivery system, ratio of ments, additional anticaries agents can include fluoride ions ingredient to encapsulating material in the delivery system, or fluorine-providing components such as inorganic fluoride average or maximum particle size of ingredient, average or salts. In some embodiments, Soluble alkali metal salts, for maximum particle size of ground delivery system, the amount example, Sodium fluoride, potassium fluoride, Sodium fluo of the ingredient or the delivery system in the compressible rosilicate, ammonium fluorosilicate, sodium monofluoro chewing gum, ratio of different polymers used to encapsulate phosphate, as well as tin fluorides, such as Stannous fluoride one or more ingredients, hydrophobicity of one or more poly 25 and Stannous chloride can be included. In some embodi mers used to encapsulate one or more ingredients, hydropho ments, a fluorine-containing compound having a beneficial bicity of the delivery system, the type oramount of coating on effect on the care and hygiene of the oral cavity, e.g., dimi the delivery system, the type or amount of coating on an nution of enamel solubility in acid and protection of the teeth ingredient prior to the ingredient being encapsulated, etc. against decay may also be included as an ingredient. In some embodiments, the release profiles of one or more 30 Examples thereof include sodium fluoride, stannous fluoride, dental care ingredients may be managed for a compressible potassium fluoride, potassium Stannous fluoride (SnF.Sub.2- gum. Such dental care ingredients (also known as oral care KF), sodium hexafluorostannate, stannous chlorofluoride, ingredients) may include but are not limited to tooth whiten Sodium fluorozirconate, and sodium monofluorophosphate. ers, stain removers, oral cleaning, bleaching agents, desensi In Some embodiments, urea is included. Further examples are tizing agents, dental remineralization agents, antibacterial 35 included in the following U.S. patents and U.S. published agents, anticaries agents, plaque acid buffering agents, Sur patent applications, the contents of all of which are incorpo factants and anticalculus agents. Non-limiting examples of rated in their entirety herein by reference for all purposes: Such ingredients can include, hydrolytic agents including U.S. Pat. No. 5,227,154 to Reynolds, U.S. Pat. No. 5,378,131 proteolytic enzymes, abrasives Such as hydrated silica, cal to Greenberg, U.S. Pat. No. 6,846,500 to Luo et al., U.S. Pat. cium carbonate, Sodium bicarbonate and alumina, other 40 No. 6,733,818 to Luo et al., U.S. Pat. No. 6,696,044 to Luo et active stain-removing components such as Surface-active al., U.S. Pat. No. 6,685,916 to Holme et al., U.S. Pat. No. agents, including, but not limited to anionic Surfactants such 6,485,739 to Luo et al., U.S. Pat. No. 6,479,071 to Holme et as Sodium Stearate, sodium palminate, Sulfated butyl oleate, al., U.S. Pat. No. 6,471,945 to Luo et al., U.S. Patent Publi Sodium oleate, salts of fumaric acid, glycerol, hydroxylated cation Nos. 2005.0025721 to Holme et al., 2005008732 to lecithin, Sodium lauryl Sulfate and chelators such as poly 45 Gebreselassie et al., and 20040136928 to Holme et al. phosphates, which are typically employed as tartar control Typically, encapsulation of the active ingredient will result ingredients. In some embodiments, dental care ingredients in a delay in the release of the predominant amount of the can also include tetrasodium pyrophosphate and Sodium tri active ingredient during consumption of a compressible polyphosphate, sodium bicarbonate, sodium acid pyrophos chewing gum that includes the encapsulated active ingredient phate, sodium tripolyphosphate, Xylitol, Sodium hexameta 50 (e.g., as part of a delivery system added as an ingredient to the phosphate. In some embodiments, peroxides such as compressible chewing gum composition). In some embodi carbamide peroxide, calciumperoxide, magnesiumperoxide, ments, the release profile of the ingredient (e.g., the dental Sodium peroxide, hydrogen peroxide, and peroxydiphospate care active ingredient) can be managed for a compressible are included. In some embodiments, potassium nitrate and gum by managing various characteristics of the ingredient, potassium citrate are included. Other examples can include 55 delivery system containing the ingredient, and/or the com casein glycomacropeptide, calcium casein peptone-calcium pressible chewing gum containing the delivery system and/or phosphate, casein phosphopeptides, casein phosphopeptide how the delivery system is made. For example, characteristics amorphous calcium phosphate (CPP-ACP), and amorphous may include one or more of the following: tensile strength of calcium phosphate. Still other examples can include papaine, the delivery system, water solubility of the ingredient, water krillase, pepsin, trypsin, lysozyme, dextranase, mutanase, 60 solubility of the encapsulating material, water solubility of glycoamylase, amylase, glucose oxidase, and combinations the delivery system, ratio of ingredient to encapsulating mate thereof. Further examples can include Surfactants such as rial in the delivery system, average or maximum particle size Sodium Stearate, Sodium ricinoleate, and sodium lauryl Sul of ingredient, average or maximum particle size of ground fate Surfactants for use in some embodiments to achieve delivery system, the amount of the ingredient or the delivery increased prophylactic action and to render the dental care 65 system in the compressible chewing gum, ratio of different ingredients more cosmetically acceptable. Surfactants can polymers used to encapsulate one or more ingredients, hydro preferably be detersive materials which impart to the compo phobicity of one or more polymers used to encapsulate one or US 8,603,440 B2 39 40 more ingredients, hydrophobicity of the delivery system, the conic acid, lactic acid, phosphoric acid, malic acid, oxalic type or amount of coating on the delivery system, the type or acid, Succinic acid, tartaric acid and combinations thereof. amount of coating on an ingredient prior to the ingredient Typically, encapsulation of a food acid will resultina delay being encapsulated, etc. in the release of the predominant amount of the active ingre In some embodiments, the release profiles of one or more dient during consumption of a compressible chewing gum flavor potentiators can be managed for a compressible gum. that includes the encapsulated food acid (e.g., as part of a Flavor potentiators can consist of materials that may inten delivery system added as an ingredient to the compressible Sify, Supplement, modify or enhance the taste and/or aroma chewing gum). In some embodiments, the release profile of perception of an original material without introducing a char the ingredient (e.g., the food acid) can be managed for a acteristic taste and/or aroma perception of their own. In some 10 compressiblegum by managing various characteristics of the embodiments, potentiators designed to intensify, Supplement, ingredient, delivery system containing the ingredient, and/or modify, or enhance the perception of flavor, Sweetness, tart the compressible chewing gum containing the delivery sys ness, umami, kokumi, Saltiness and combinations thereof can tem and/or how the delivery system is made. For example, be included. In some embodiments, Sweetness may be poten characteristics may include one or more of the following: tiated by the inclusion of monoammonium glycyrrhizinate, 15 tensile strength of the delivery system, water solubility of the licorice glycyrrhizinates, citrus aurantium, maltol, ethyl mal ingredient, water Solubility of the encapsulating material, tol, Vanilla, Vanillin, and combinations thereof. In some water solubility of the delivery system, ratio of ingredient to embodiments, Sugar acids, Sodium chloride, potassium chlo encapsulating material in the delivery system, average or ride, Sodium acid sulfate, and combinations thereof may be maximum particle size of ingredient, average or maximum included for flavor potentiation. In other examples, particle size of ground delivery system, the amount of the glutamates such as monosodium glutamate (MSG), monopo ingredient or the delivery system in the compressible chewing tassium glutamate, hydrolyzed vegetable protein, hydrolyzed gum, ratio of different polymers used to encapsulate one or animal protein, yeast extract, and combinations thereof are more ingredients, hydrophobicity of one or more polymers included. Further examples can include glutathione, and used to encapsulate one or more ingredients, hydrophobicity nucleotides Such as inosine monophosphate (IMP), disodium 25 of the delivery system, the type or amount of coating on the inosinate, Xanthosine monophosphate, guanylate monophos delivery system, the type or amount of coating on an ingre phate (GMP), and combinations thereof. Forbitterness block dient prior to the ingredient being encapsulated, etc. ing or taste masking, ingredients that interact with bitterness In some embodiments, the release profiles of one or more receptors to Suppress bitterness or off tastes may be included. micronutrients can be managed for a compressible gum. In some embodiments, adenosine monophosphate (AMP) 30 Micronutrients can include materials that have an impact on can be included for bitterness suppression. Bitterness modi the nutritional wellbeing of an organism even though the fication can also be accomplished by using Sweetness or quantity required by the organism to have the desired effect is flavors with complementary bitter notes Such as chocolate. Small relative to macronutrients such as protein, carbohy Further examples of flavor potentiator compositions that drate, and fat. Micronutrients can include, but are not limited impart kokumi are also included in U.S. Pat. No. 5,679.397 to 35 to vitamins, minerals, enzymes, phytochemicals, antioxi Kuroda et al., the entire contents of which are incorporated in dants, and combinations thereof. In some embodiments, Vita its entirety herein by reference. mins can include fat soluble vitamins such as vitamin A, Typically, encapsulation of a flavor potentiator will result Vitamin D. Vitamin E, and vitamin K and combinations in a delay in the release of the predominant amount of the thereof, in some embodiments, vitamins can include water flavor potentiator during consumption of a compressible 40 soluble vitamins such as vitamin C (ascorbic acid), the B chewing gum that includes the encapsulated flavor potentia vitamins (thiamine or B1, riboflavoin or B2, niacin or B3, tor (e.g., as part of a delivery system added as an ingredient to pyridoxine or B6, folic acid or B9, cyanocobalimin or B12, the compressible chewing gum composition). In some pantothenic acid, biotin), and combinations thereof. embodiments, the release profile of the ingredient (e.g., the In some embodiments, minerals can include but are not flavor potentiator) can be managed for a compressiblegum by 45 limited to sodium, magnesium, chromium, iodine, iron, man managing various characteristics of the ingredient, delivery ganese, calcium, copper, fluoride, potassium, phosphorous, system containing the ingredient, and/or the compressible molybdenum, selenium, Zinc, and combinations thereof. chewing gum containing the delivery system and/or how the In some embodiments micronutrients can include but are delivery system is made. For example, characteristics may not limited to L-carnitine, choline, coenzyme Q10, alpha include one or more of the following: tensile strength of the 50 lipoic acid, omega-3-fatty acids, pepsin, phytase, trypsin, delivery system, water solubility of the ingredient, water lipases, proteases, cellulases, and combinations thereof. solubility of the encapsulating material, water solubility of Antioxidants can include materials that scavenge free radi the delivery system, ratio of ingredient to encapsulating mate cals. In some embodiments, antioxidants can include but are rial in the delivery system, average or maximum particle size not limited to ascorbic acid, citric acid, rosemary oil, Vitamin of ingredient, average or maximum particle size of ground 55 A. vitamin E. Vitamin E phosphate, tocopherols, di-alpha delivery system, the amount of the ingredient or the delivery tocopheryl phosphate, tocotrienols, alpha lipoic acid, dihy system in the compressible chewing gum, ratio of different drolipoic acid, Xanthophylls, beta cryptoxanthin, lycopene, polymers used to encapsulate one or more ingredients, hydro lutein, Zeaxanthin, astaxanthin, beta-carotene, carotenes, phobicity of one or more polymers used to encapsulate one or mixed carotenoids, polyphenols, flavonoids, and combina more ingredients, hydrophobicity of the delivery system, the 60 tions thereof. type or amount of coating on the delivery system, the type or In some embodiments, phytochemicals can include but are amount of coating on an ingredient prior to the ingredient not limited to cartotenoids, chlorophyll, chlorophyllin, fiber, being encapsulated, etc. flavanoids, anthocyanins, cyaniding, delphinidin, malvidin, In some embodiments, the release profiles of one or more pelargonidin, peonidin, petunidin, flavanols, catechin, epicat acids may be managed for a compressible gum. Acids can 65 echin, epigallocatechin, epigallocatechingallate, theaflavins, include, but are not limited to acetic acid, adipic acid, ascorbic thearubigins, proanthocyanins, flavonols, quercetin, acid, butyric acid, citric acid, formic acid, fumaric acid, gly kaempferol, myricetin, isorhamnetin, flavononeshesperetin, US 8,603,440 B2 41 42 naringenin, eriodictyol, tangeretin, flavones, apigenin, luteo includes the encapsulated mouth moistening agent (e.g., as lin, lignans, phytoestrogens, resveratrol, isoflavones, daid part of a delivery system added as an ingredient to the com Zein, genistein, glycitein, Soy isoflavones, and combinations pressible chewing gum). In some embodiments, the release thereof. profile of the ingredient (e.g., the mouth moistening agent) Typically, encapsulation of the micronutrient will result in can be managed for a compressiblegum by managing various a delay in the release of the predominant amount of the active characteristics of the ingredient, delivery system containing ingredient during consumption of a compressible chewing the ingredient, and/or the compressible chewing gum con gum that includes the encapsulated micronutrient (e.g., as taining the delivery system and/or how the delivery system is part of a delivery system added as an ingredient to the com made. For example, characteristics may include one or more pressible chewing gum). In some embodiments, the release 10 profile of the ingredient (e.g., the micronutrient) can be man of the following: tensile strength of the delivery system, water aged for a compressible gum by managing various character solubility of the ingredient, water solubility of the encapsu istics of the ingredient, delivery system containing the ingre lating material, water solubility of the delivery system, ratio dient, and/or the compressible chewing gum containing the of ingredient to encapsulating material in the delivery system, delivery system and/or how the delivery system is made. For 15 average or maximum particle size of ingredient, average or example, characteristics may include one or more of the fol maximum particle size of ground delivery system, the amount lowing: tensile strength of the delivery system, water solubil of the ingredient or the delivery system in the compressible ity of the ingredient, water Solubility of the encapsulating chewing gum, ratio of different polymers used to encapsulate material, water solubility of the delivery system, ratio of one or more ingredients, hydrophobicity of one or more poly ingredient to encapsulating material in the delivery system, mers used to encapsulate one or more ingredients, hydropho average or maximum particle size of ingredient, average or bicity of the delivery system, the type oramount of coating on maximum particle size of ground delivery system, the amount the delivery system, the type or amount of coating on an of the ingredient or the delivery system in the compressible ingredient prior to the ingredient being encapsulated, etc. chewing gum, ratio of different polymers used to encapsulate In some embodiments, the release profiles of one or more one or more ingredients, hydrophobicity of one or more poly 25 ingredients that soothe the throat can be managed for a com mers used to encapsulate one or more ingredients, hydropho pressible gum. Throat soothing ingredients can include anal bicity of the delivery system, the type oramount of coating on gesics, anesthetics, demulcents, antiseptic, and combinations the delivery system, the type or amount of coating on an thereof. In some embodiments, analgesics/anesthetics can ingredient prior to the ingredient being encapsulated, etc. include menthol, phenol, hexylresorcinol, benzocaine, dyclo In some embodiments, the release profiles of one or more 30 nine hydrochloride, benzyl alcohol, salicylalcohol, and com mouth moisteners can be managed for a compressible gum. binations thereof. In some embodiments, demulcents can Mouth moisteners can include, but are not limited to, saliva include but are not limited to slippery elm bark, pectin, gela stimulators such as acids and salts and combinations thereof. tin, and combinations thereof. In some embodiments, anti In some embodiments, acids can include acetic acid, adipic septic ingredients can include cetylpyridinium chloride, acid, ascorbic acid, butyric acid, citric acid, formic acid, 35 domiphen bromide, dequalinium chloride, and combinations fumaric acid, glyconic acid, lactic acid, phosphoric acid, thereof. malic acid, oxalic acid. Succinic acid, tartaric acid and com In some embodiments, antitussive ingredients such as binations thereof. Mouth moisteners can also include hydro chlophedianol hydrochloride, codeine, codeine phosphate, colloid materials that hydrate and may adhere to oral Surface codeine Sulfate, dextromethorphan, dextromethorphan to provide a sensation of mouth moistening. Hydrocolloid 40 hydrobromide, diphenhydramine citrate, and diphenhy materials can include naturally occurring materials such as dramine hydrochloride, and combinations thereof can be plant exudates, seed gums, and seaweed extracts or they can included. be chemically modified materials such as cellulose, starch, or In Some embodiments, throat soothing agents such as natural gum derivatives. In some embodiments, hydrocolloid honey, propolis, aloe Vera, glycerine, menthol and combina materials can include pectin, gum arabic, acacia gum, algi 45 tions thereof can be included. In still other embodiments, nates, agar, carageenans, guar gum, Xanthan gum, locust bean cough Suppressants can be included. Such cough Suppres gum, gelatin, gellan gum, galactomannans, tragacanth gum, sants can fall into two groups: those that alter the texture or karayagum, curdlan, konjac, chitosan, Xyloglucan, beta glu production of phlegm. Such as mucolytics and expectorants; can, furcellaran, gum ghatti, tamarin, bacterial gums, and and those that Suppress the coughing reflex Such as codeine combinations thereof. Additionally, in Some embodiments, 50 (narcotic cough Suppressants), antihistamines, dextrometho modified natural gums such as propylene glycol alginate, rphan and isoproterenol (non-narcotic cough suppressants). carboxymethyl locust bean gum, low methoxyl pectin, and In Some embodiments, ingredients from either or both groups their combinations can be included. In some embodiments, can be included. modified celluloses can be included Such as microcrystalline In still other embodiments, antitussives can include, but are cellulose, carboxymethlcellulose (CMC), methylcellulose 55 not limited to, the group consisting of codeine, dextrometho (MC), hydroxypropylmethylcellulose (HPMC), and hydrox rphan, dextrorphan, diphenhydramine, hydrocodone, nos ypropylcellulose (MPC), and combinations thereof. Simi capine, oxycodone, pentoxyverine and combinations thereof. larly, humectants which can provide a perception of mouth In some embodiments, antihistamines can include, but are not hydration can be included. Such humectants can include, but limited to, acrivastine, azatadine, brompheniramine, chlo are not limited to glycerol, Sorbitol, polyethylene glycol, 60 phiheniramine, clemastine, cyproheptadine, dexbromphe erythritol, and Xylitol. Additionally, in Some embodiments, niramine, dimenhydrinate, diphenhydramine, doxylamine, fats can provide a perception of mouth moistening. Such fats hydroxy Zine, meclizine, phenindamine, phenyltoloxamine, can include medium chain triglycerides, vegetable oils, fish promethazine, pyrilamine, tripelennamine, triprolidine and oils, mineral oils, and combinations thereof. Typically, encap combinations thereof. In some embodiments, non-sedating Sulation of a mouth moistening agent will result in a delay in 65 antihistamines can include, but are not limited to, astemizole, the release of the predominant amount of the active ingredient cetirizine, ebastine, fexofenadine, loratidine, terfenadine, and during consumption of a compressible chewing gum that combinations thereof. US 8,603,440 B2 43 44 In some embodiments, expectorants can include, but are (E161b), cochineal extract (E120); carmine (E132), car not limited to, ammonium chloride, guaifenesin, ipecac fluid moisinefazorubine (E122), sodium copper chlorophyllin extract, potassium iodide and combinations thereof. In some (E141), chlorophyll (E140), toasted partially defatted cooked embodiments, mucolytics can include, but are not limited to, cottonseed flour, ferrous gluconate, ferrous lactate, grape acetylcycsteine, ambroXol, bromhexine and combinations color extract, grape skin extract (enocianina), anthocyanins thereof. In some embodiments, analgesic, antipyretic and (E163), haematococcus algae meal, synthetic iron oxide, iron anti-inflammatory agents can include, but are not limited to, oxides and hydroxides (E172), fruit juice, vegetable juice, acetaminophen, aspirin, diclofenac, diflunisal, etodolac, dried algae meal, tagetes (AZtec marigold) meal and extract, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, ketorolac, carrot oil, corn endosperm oil, paprika, paprika oleoresin, nabumetone, naproxen, piroXicam, caffeine and mixtures 10 phaffia yeast, riboflavin (E101), saffron, titanium dioxide, thereof. In some embodiments, local anesthetics can include, turmeric (E100), turmeric oleoresin, amaranth (E123), cap but are not limited to, lidocaine, benzocaine, phenol, dyclo santhin/capsorbin (E160c), lycopene (E160d), and combina nine, benzonotate and mixtures thereof. In some embodi tions thereof. ments nasal decongestants and ingredients that provide the In some embodiments, certified colors can include, but are perception of nasal clearing can be included. In some embodi 15 not limited to, FD&C blue #1, FD&C blue #2, FD&C green ments, nasal decongestants can include but are not limited to #3, FD&C red #3, FD&C red #40, FD&C yellow #5 and phenylpropanolamine, pseudoephedrine, ephedrine, phe FD&C yellow #6, tartrazine (E102), quinoline yellow nylephrine, oxymetazoline, and combinations thereof. In (E104), sunset yellow (E110), ponceau (E124), erythrosine Some embodiments ingredients that provide a perception of (E127), patent blue V (E131), titanium dioxide (E171), alu nasal clearing can include but are not limited to menthol, minum (E173), silver (E174), gold (E175), pigment rubine/ camphor, borneol, ephedrine, eucalyptus oil, peppermint oil, lithol rubine BK (E180), calcium carbonate (E170), carbon methyl salicylate, bornyl acetate, lavender oil, wasabi black (E153), black PN/brilliant black BN (E151), green extracts, horseradish extracts, and combinations thereof. In S/acid brilliant green BS (E142), and combinations thereof. Some embodiments, a perception of nasal clearing can be In some embodiments, certified colors can include FD&C provided by odoriferous essential oils, extracts from woods, 25 aluminum lakes. These consist of the aluminum salts of gums, flowers and other botanicals, resins, animal secretions, FD&C dyes extended on an insoluble substrate of alumina and synthetic aromatic materials. hydrate. Additionally, in some embodiments, certified colors Typically, encapsulation of a throat care agent will result in can be included as calcium salts. Typically, encapsulation of a delay in the release of the predominant amount of the active a color will result in a delay in the release of the predominant ingredient during consumption of a compressible chewing 30 amount of the active ingredient during consumption of a gum that includes the encapsulated throat care agent (e.g. as compressible chewing gum that includes the encapsulated part of a delivery system added as an ingredient to the com color (e.g., as part of a delivery system added as an ingredient pressible chewing gum). In some embodiments, the release to the compressible chewing gum). In some embodiments, the profile of the ingredient (e.g. the dental care active ingredient) release profile of the ingredient (e.g., the color) can be man can be managed for a compressiblegum by managing various 35 aged by managing various characteristics of the ingredient, characteristics of the ingredient, delivery system containing delivery system containing the ingredient, and/or the com the ingredient, and/or the compressible chewing gum con pressible chewing gum containing the delivery system and/or taining the delivery system and/or how the delivery system is how the delivery system is made. For example, characteristics made. For example, characteristics may include one or more may include one or more of the following: tensile strength of of the following: tensile strength of the delivery system, water 40 the delivery system, water solubility of the ingredient, water solubility of the ingredient, water solubility of the encapsu solubility of the encapsulating material, water solubility of lating material, water solubility of the delivery system, ratio the delivery system, ratio of ingredient to encapsulating mate of ingredient to encapsulating material in the delivery system, rial in the delivery system, average or maximum particle size average or maximum particle size of ingredient, average or of ingredient, average or maximum particle size of ground maximum particle size of ground delivery system, the amount 45 delivery system, the amount of the ingredient or the delivery of the ingredient or the delivery system in the compressible system in the compressible chewing gum, ratio of different chewing gum, ratio of different polymers used to encapsulate polymers used to encapsulate one or more ingredients, hydro one or more ingredients, hydrophobicity of one or more poly phobicity of one or more polymers used to encapsulate one or mers used to encapsulate one or more ingredients, hydropho more ingredients, hydrophobicity of the delivery system, the bicity of the delivery system, the type oramount of coating on 50 type or amount of coating on the delivery system, the type or the delivery system, the type or amount of coating on an amount of coating on an ingredient prior to the ingredient ingredient prior to the ingredient being encapsulated, etc. being encapsulated, etc. In some embodiments, one or more colors can be included. In some embodiments, a delivery system or compressible As classified by the United States Food, Drug, and Cosmetic chewing gum may include two or more ingredients for which Act (21 C.F.R. 73), colors can include exempt from certifica 55 managed release from the compressible chewing gum during tion colors (sometimes referred to as natural even though they consumption of the compressible chewing gum is desired. In can be synthetically manufactured) and certified colors Some embodiments, the ingredients may be encapsulated or (sometimes referred to as artificial), or combinations thereof. otherwise included separately in different delivery systems. In some embodiments, exempt from certification or natural Alternatively, in some embodiments the ingredients may be colors can include, but are not limited to annatto extract, (E 60 encapsulated or otherwise included in the same delivery sys 160b), bixin, norbixin, astaxanthin, dehydrated beets (beet tem. As another possibility, one or more of the ingredients powder), beetroot red/betanin (E162), ultramarine blue, can may be free (e.g. unencapsulated) while one or more other thaxanthin (E161g), cryptoxanthin (E161c), rubixanthin ingredients may be encapsulated. A compressible chewing (E161d), violanxanthin (E161e), rhodoxanthin (E161f), cara gum may include a group of ingredients for which managed mel (E150(a-d)), B-apo-8-carotenal (E160e), B-carotene 65 release of the group during consumption of the compressible (E160a), alpha carotene, gamma carotene, ethyl ester of beta chewing gum is desired. Groups of two or more ingredients apo-8 carotenal (E160f), fiavoxanthin (E161a), lutein for which managed release from a compressible chewing gum US 8,603,440 B2 45 46 during consumption of the compressible chewing gum may be part of the same delivery system or may be part of different be desired include, but are not limited to: color and flavor, delivery systems. Different delivery systems may use the multiple flavors, multiple colors, cooling agent and flavor, same or different encapsulating materials. Warming agent and flavor, cooling agent and warming agent, Typically, encapsulation of the multiple ingredients will cooling agent and high-intensity Sweetener, warming agent result in a delay in the release of the predominant amount of and high-intensity Sweetener, multiple cooling agents (e.g., the multiple ingredients during consumption of a compress WS-3 and WS-23, WS-3 and menthyl succinate), menthol ible chewing gum that includes the encapsulated multiple and one or more cooling agents, menthol and one or more ingredients (e.g. as part of a delivery system added as an warming agents, multiple warming agents, high-intensity ingredient to the compressible chewing gum). This may be Sweetener(s) and tooth whitening active(s), high-intensity 10 particularly helpful in situations wherein separate encapsula Sweetener(s) and breath-freshening active(s), an ingredient tion of the ingredients may cause them to release with differ with some bitterness and a bitterness Suppressor for the ingre ent release profiles. For example, different high-intensity dient, multiple high-intensity Sweeteners (e.g., acesulfame-k sweeteners may have different release profiles because they and aspartame), multiple tooth whitening active ingredients have different water solubilities or differences in other char (e.g., an abrasive ingredient and an antimicrobial ingredient, 15 acteristics. Encapsulating them together may cause them to a peroxide and a nitrate, a warming agent and a polyol, a release more simultaneously. cooling agent and a polyol, multiple polyols, a warming agent In some embodiments, the release profile of the multiple and micronutrient, a cooling agent and a micronutrient, a ingredients can be managed for a compressible gum by man Warming agent and a mouth moistening agent, a cooling agent aging various characteristics of the multiple ingredients, the and a mouth moistening agent, a warming agent and a throat delivery system containing the multiple ingredients, and/or care agent, a cooling agent and a throat care agent, a warming the compressible chewing gum containing the delivery sys agent and a food acid, a cooling agent and food acid, a warm tem and/or how the delivery system is made in a manner as ing agent and an emulsifier/surfactant, a cooling agent and an previously discussed above. emulsifier/surfactant, a warming agent and a color, a cooling The active ingredients mentioned above are meant as agent and a color, a warming agent and a flavor potentiator, a 25 examples of active ingredients which could be applicable in a cooling agent and a flavor potentiator, a warming agent with chewing gum granule or compressed chewing gum, however, Sweetness potentiator, a cooling agent with a Sweetness this list should not be considered as exhaustive. potentiator, a warming agent and an appetite Suppressant, a Active ingredients to be applied in tablets according to cooling agent and an appetite Suppressant, a high-intensity embodiments of the invention may be applied as such or be Sweetener and a flavor, a cooling agent and a teeth-whitening 30 included or bonded in different ways, such as being part of an agent, a warming agent and a teeth-whitening agent, a warm inclusion complex e.g. as described in U.S. Pat. No. 5,866, ing agent and breath-freshening agent, a cooling agent and a 179, which is hereby incorporated by reference. A resin breath-freshening agent, a cooling agent and an effervescing bonding of nicotine is described in e.g. WO 2006/000232 system, a warming agent and an effervescing system, a warm which is also incorporated herein by reference. Further con ing agent and an antimicrobial agent, a cooling agent and an 35 ventional methods of applying active ingredients may obvi antimicrobial agent, multiple anticalcums ingredients, mul ously be applied within the scope of the invention. tiple remineralization ingredients, multiple Surfactants, rem The active ingredients may advantageously be applied in a ineralization ingredients with demineralization ingredients, gum base-containing module or a tablet-module Substantially acidic ingredients with acid buffering ingredients, anticalcu free of gum base depending on the applied type of active lus ingredients with antibacterial ingredients, remineraliza 40 ingredient. If the active ingredient is of the pharmaceutical tion ingredients with anticalculus ingredients, anticalculus type, such ingredient may very often advantageously be com ingredients with remineralization ingredients with antibacte prised in a tablet module substantially free of gum base rial ingredients, Surfactant ingredients with anticalculus whereas taste relevantactive ingredients advantageously may ingredients, Surfactant ingredients with antibacterial ingredi be added to the gum base-containing module and very often to ents, Surfactant ingredients with remineralization ingredi 45 both types of modules. The taste relevant active ingredient ents, Surfactants with anticalculus ingredients with antibac may both be added as separate particles which are mixed and terial ingredients, multiple types of Vitamins or minerals, compressed with gum base-containing particles in one mod multiple micronutrients, multiple acids, multiple antimicro ule and it may be incorporated into gum base-containing bial ingredients, multiple breath-freshening ingredients, granules. breath-freshening ingredients and antimicrobial ingredients, 50 In the present context, the terms granule and particle are multiple appetite Suppressors, acids and bases that react to used interchangeable in the sense that a granule or particle for effervesce, a bitter compound with a high-intensity Sweet use in a compression process is regarded to be a relatively ener, a cooling agent and an appetite Suppressant, a warming Small object, which together with other granules or particles agent and an appetite Suppressant, a high-intensity Sweetener may be compressed into a stable chewing gum tablet. The and an appetite Suppressant, a high-intensity Sweetener with 55 granules or particles may be produced in several different an acid, a probiotic ingredient and a prebiotic ingredient, a ways. A gum base-containing granule of particle may typi Vitamin and a mineral, a metabolic enhancement ingredient cally be produced substantially into the desired shape by with a macronutrient, a metabolic enhancement ingredient means of an extrusion process or alternatively be produced on with a micronutrient, an enzyme with a Substrate, a high the basis of a gum base-containing mass which is Subse intensity Sweetener with a Sweetness potentiator, a cooling 60 quently separated into particles of a smaller size. compound with a cooling potentiator, a flavor with a flavor The following non-limiting examples illustrate different potentiator, a warming compound with a warming potentia variations of compressed chewing gum tablets comprising tor, a flavor with salt, a high-intensity Sweetener with salt, an one or more pharmaceutically active ingredients and their acid with salt, a cooling compound with salt, a warming corresponding enhancers. The examples are meant for indi compound with salt, a flavor with a surfactant, an astringent 65 cating the inventive concept; hence the mentioned examples compound with an ingredient to provide a sensation of hydra should not be understood as exhaustive for the present inven tion, etc. In some embodiments, the multiple ingredients may tion. US 8,603,440 B2 47 48 Example 1 The composition is extruded through the die plate, which is here a die plate having 696 holes with a diameter of 0.36 mm Preparation of Gum Base and Preparation of and being heated to a temperature of about 177° C. In the Granules and Finely Grinded Particles Based granulator chamber the extruded composition is cut to gran Thereon 5 ules by a cutter with 8 blades and cutter speed set at 1999 rpm. Gum base is prepared with a content of absorption The particles are cooled and transported to the strainer unit enhancer and gum base is prepared without a content of (here a centrifugal dryer TWS 20, available from GALA absorption enhancer. There are applied enhancers such as pH GmbH, Germany) in water with temperature about 11° C. and flow about 22 m/h. The average cooling and transport time in control agents as shown in the compositions outlined in table 10 1. water is approx. 60 seconds. The particle rate is 400 kg/hand the average diameter of the obtained particles is here obtained TABLE 1. to be 0.93 mm. The cooling and transport stage carried out in water in this Gum base compositions. Amounts are given in percent by example could be carried out in other media such as e.g. air as weight of each composition. 15 well. Also various alternative apparatuses, die plates, settings, Component GB 1 GB 2 etc. could be applied in order to obtain smaller or larger Elastomer 10 10 average particle sizes of the prepared granules. PVA 21 21 The granules are applied in the compressed chewing gum Natural resin 29 29 2O according to the below examples. Filler 9 16.5 Na2CO3-pH control agent 7.5 O Part of the granules are cooled to about -30°C. and further Emulsifier 4 4 grinded in a mill to obtain Smaller particles having diameters Softener (wax and fat) 19.4 19.4 mostly below about 600 um and on average about 250-300 Antioxidant O.1 O.1 (900 ppm) (900 ppm) um. These finely grinded gum base particles are “landed' and 25 stored in bulk sweetener in order to reduce their sticking together. The temperature of the particles at outlet from the The preparation of the gum base is carried out by first mill is about 5 to 15°C. The amount of bulk sweetenerapplied adding elastomer, polyvinyl acetate, filler and sodium car here is about 10-20% by weight of the total weight of the bonate to a heated (about 120°C.) and running Z-blade mixer. mixture of bulk sweetener and gum base particles. Other After about twenty minutes of mixing, natural resin is added 30 materials with Stickiness-reducing abilities could alterna to the running mixer and mixing is continued for about five tively be applied. minutes followed by addition of further natural resin. After about five minutes of continued mixing, emulsifier and fur Example 2 ther elastomer are added to the running mixer, and mixing is continued for about five minutes before addition of softener 35 and antioxidant to the running mixer. Mixing is continued for Single Line Binding API with Flavor about half an hour to one hour, and the final gum base mass is emptied from the mixer into coated or lined pans, extruded or The API (API: pharmaceutically active ingredient), in this cast into any desirable shape. Those skilled in the art will example NPR, was dispersed in a mixture of grinded chewing recognize that many variations of the above-described proce 40 gum granules and isomalt in a ratio of approximately 2:3. dure may be followed. In a next step 1.0 Wt-% peppermint flavor was sprayed into To form the gum base as granules, the prepared gum base is the powder mixture from a nozzle, whereby the NPR was transferred either directly or in the form of pellets to an glued to both the grinded chewing gum granules and the extruder (here a Leistritz ZSE/BL 360kw 104, available from isomalt. Leistritz GmbH, Germany), which extrudes the gum base 45 In a next step the resulting mixture was sieved through an through a die plate into a liquid filled chamber (here a granu 800 um sieve in order to remove larger cloggings. lator A5 PAC 6, available from GALA GmbH, Germany). The resulting product was a mixture of not very distinctly Descriptions of the extruder and the granulator may be found sized granules with NPR bound to both grinded chewing gum in e.g. WO 2004/098305, incorporated herein by reference. granules and to isomalt, whereby an improved mixing was The already prepared gum base composition is added at a 50 facilitated first inlet of the extruder. Menthol flavor crystals in an amount of about 3% by weight of the gum base is dosed to a second Example 3 inlet and mixed into the gum base composition in the extruder. The addition of menthol could be omitted to form gum base Dual Line Binding API with Flavor granules entirely based on the already prepared gum base. 55 However, an improved taste and texture of the granules can be The API (API: pharmaceutically active ingredient), in this obtained by adding additional ingredients such as the above example NPR, was dispersed with an isomalt composition. or other flavors or additives. In a next step 1.0 Wt-% peppermint flavor was sprayed into The extruder delivers the gum base-comprising composi the powder mixture from a nozzle, whereby the NPR was tion at a feed rate of 400 kg/h to the die plate. An extruder 60 attached to the surface of the isomalt. screw speed set at 247 rpm is applied, and the temperature in Hereby particles with an approximate diameter, corre the extruder is in the range of 40°C. to 70° C. along about 34 sponding to the approximate diameter of the chewing gum of the extruder barrel length, until the composition passes a granules to be used in the same module, were obtained, and heating device in the outlet end of the extruder. Here the Subsequently a desired amount of chewing gum granules composition is heated to an extruder exit temperature of about 65 were added to obtain a resulting mixture. 109° C. The extruder and the granulator produce a pressure The resulting product was a mixture of not very distinctly difference of about 70-75 bar. sized granules of which Some were chewing gum granules US 8,603,440 B2 49 50 and some were isomalt with bound NPR, whereby an TABLE 2 improved mixing was facilitated. Chewing gum compositions of 1-layer Example 4 chewing gum tablets comprising pharmaceutically active ingredients. Amounts are given in percent by weight of each composition. 5 Dry Binding an API in the Pores or the Irregular Chewing Chewing Chewing Chewing Surface of a Dry Binder by Means of an Ordered gun gun gun gun Blending Process composition composition composition composition Component A. B C D

The powder blend was produced in an ordered blending 10 GB 1 of 40.O 2 2 O process where the ingredients were blended in a specific example 1 order. The pharmaceutically active ingredient (API), in this GB 2 of O 38.0 38.0 40.O example 1 example NPR, was mixed with a dry binder, in this example Bulk Sweetener 57.39 39.3 57.7 58.47 a dextrate consisting of large porous particles. The API was NPR with 1.11 O O O bound physically in the pores of the dry binder by Van der 15 nicotine load 15.3% Waal forces or electrostatic forces to a degree in order for Metformin O 19.2 O O segregation to be avoided. In a next step the resulting spaces Ceterizine O O O.8 O between the dry binders were filled up by isomalt. Exenatide O O O O.O3 Dry binders for use in a method like described here will Flavor O.S O.S O.S O.S typically have an average diameter of approximately 190 to Tabletting aid 1.O 1.O 1.O 1.O 220 Lum. The resulting product was a dry bound NPR powder blend Four different ways of mixing the chewing gum composi with an approximate diameter corresponding to the approxi tions of table 2 are applied. mate diameter of the grinded gum base. In this mixture/ The chewing gum tablets obtained from the compositions composition segregation is reduced to an acceptable level due 25 mixed in the three different ways are referred to as chewing to the more equal sizes and due to the dry binder mechanism. gum tablets A1, B1, C1, D1: A2, B2, C2, D2; A3, B3, C3, D3; It should be noted, that by “more equal sizes it is not meant A4, B4, C4, D4, respectively. that the particle sizes do actually have to be equal or almost Subsequent to a first manner of mixing the chewing gum equal, but it is meant that the difference in particle size has been significantly reduced as compared to NPR particles by 30 compositions, the compositions are compressed to form themselves in blend with the chewing gum granules. chewing gum tablets A1, B1, C1 and D1: Gum base in the form of granules of example 1 is blended Example 5 with bulk Sweetener, pharmaceutically active ingredient, fla 35 Vorandtabletting aid to form the chewing gum compositions. Dry Binding an API by Means of Adhesive Contact The chewing gum compositions are compressed in a tablet to the Dry Binder ting press to form the chewing gum tablets. Tablet weights are A dry binding process as in example 4 was repeated with adjusted to 1300 g. the modification that small dry binder particles were now Subsequent to a second manner of mixing the chewing gum used, in this example a copovidone. Hereby the dry binding is 40 compositions, the compositions are compressed to form the result of small dry binders which fill the spaces between chewing gum tablets A2, B2, C2, and D2: e.g. the NPR and the further ingredients such as isomalt and The chewing gum compositions are prepared by providing mannitol. With smaller dry binders the dry binder particles each gum base in the form of finely grinded particles accord are able to establish several adhesive contacts with the API 45 ing to example 1 and blending with bulk Sweetener, pharma and the further ingredients. ceutically active ingredient, flavor and tabletting aid. The Dry binders for use in a method like described here will chewing gum compositions are compressed in a tabletting typically have an average diameter of approximately 65 to 75 press to form the chewing gum tablets. Tablet weights are lm. adjusted to 1300 g. The resulting product was a dry bound NPR powder blend 50 Subsequent to a third manner of mixing the compositions, with an approximate diameter corresponding to the approxi the compositions are compressed to form chewing gum tab mate diameter of the grinded gum base. lets A3, B3, C3, and D3: Another method of dry binding knownto the skilled person The pharmaceutically active ingredients of each composi may be used within the scope of the present invention. The 55 tion are dispersed in a mixture offinely grinded chewing gum method is known as a Carrier Mixing in which a dry binder granules and bulk Sweetener particles according to the with an average diameter of approximately 75 to 150 um (e.g. amounts given in table 2. The pharmaceutically active ingre Mannitol EZ) is used. Here the active ingredient is binded in dients are bound as described in example 2 for NPR. The the internal space of the dry binder particles. chewing gum compositions are then prepared by blending the 60 Example 6 tabletting aid and the mixture of the bulk sweetener particles, flavor, pharmaceutically active ingredients and the finely One Layer Tablets grinded gum base particles. Satisfactorily even distributions of the pharmaceutically active ingredients are obtained in the One-layer tablets with contents of different pharmaceuti 65 chewing gum compositions. The chewing gum compositions cally active ingredients are prepared with the compositions are compressed in a tabletting press. Tablet weights are given in table 2. adjusted to 1300 g. US 8,603,440 B2 51 52 Subsequent to a fourth manner of mixing the compositions, The compositions of layer 1 are obtained by blending the the compositions are compressed to form chewing gum tab gum base granules, bulk Sweetener, and enhancer for each composition. The compositions of layer 2 are mixed accord lets A4, B4, C4, and D4: ing to the manners of mixing described in example 6 for one-layer tablets. The chewing gum tablets are compressed in The pharmaceutically active ingredients of each composi a tabletting press. tion are dispersed as described in example 3 for NPR. The The provided 2-layer tablets shows superior qualities as obtained chewing gum compositions have satisfactorily even regards stability during storage as compared with the 1-layer distributions of the pharmaceutically active ingredients. The tablets in those tablets where pharmaceutically active ingre chewing gum compositions are compressed in a tabletting 10 dient and pH control agent have been separated in the two press. Tablet weights are adjusted to 1300 g. layers. Example 9 The release of the pharmaceutically active ingredients from chewing gum tablets A2, A3, B2, B3, C2, C3, D2, and Multi-Layer Tablets D3 is comparable to the release of the same pharmaceutically 15 Multi-layer tablets comprising three, four or more layers or active ingredients from conventionally mixed chewing gums. modules are also prepared according to embodiments of the invention. The additional layers besides the two layers seen in Example 7 the previous examples may be further chewing gum layers and/or layers not containing gum base. One-Layer Tablets Some examples of compositions of three- and four-layered tablets are provided in table 4. The numbering of the layers The compositions given in table 2 are modified by substi does not necessarily indicate the order of the layers in the final tuting a part of the bulk Sweetener in each composition for an tablets. amount of dry-binder corresponding to 10% by weight of the chewing gum composition. 25 TABLE 4 With reference to examples 4 and 5, the composition is Chewing gum compositions. Amounts are mixed and compressed in a tabletting press to form one-layer given in percent by weight of each composition. “granules of ex. 1 tablets as outlined in example 6. refers to the larger sized granules, while finely grinded granules of ex. 1 refers to the Smaller sized, finely grinded granules of example 1. 30 Example 8 Composition no. Two-Layer Tablets Components L M N O Layer 1 Two-layer tablets with contents of pharmaceutically active 35 ingredients and absorption enhancers are prepared with the GB 1, granules of ex. 1 14.50 17.31 17.31 17.31 compositions given in table 3. Bulk Sweetener 2O.S1 26.53 26.53 26.53 TABLE 3 Chewing gum compositions of 2-layer chewing gum tablets comprising pharmaceutically active ingredients. Amounts are given in percent by weight of each composition. “granules of ex. 1 refers to the larger sized granules, while “finely grinded granules of ex. 1 refers to the Smaller sized, finely grinded granules of example 1. Composition no.

Components E F G H I J K Layer 1, weight mg 1OOO 1OOO 900 900 1OOO 1OOO 1OOO GB 1, granules of ex. 1 30.7 1 27.7 O 30.7 31.4 1 GB 2, granules of ex. 1 O 29.7 O 27.7 O O 29.2 Bulk Sweetener 45.02 46.22 40.73 41.53 46.14 40.03 41.19 Na2CO3 powder 1.2 O O.8 O O O O Polysorbate 80 O O O O O O O.04 Sodium gluconate O O O O O.04 O O Sodium laurylsulfate O O O O O.04 O O Layer 2, weight mg 3OO 300 400 400 300 4OO 400 GB 2, finely grinded 9.2 9.2 1231 O O 9.2 9.2 granules of ex. 1 GB 2, granules of ex. 1 O O O 12.31 O O O Bulk Sweetener 11.54 11.81 16.04 16.31 2.65 17.03 17.23 NPR with nicotine load 1.11 O 1.11 O O 1.11 1.11 5.3% Metformin O O O O 19.2 O O Ceterizine O O.8 O O.8 O O O.8 Polysorbate 80 O O.04 O O.04 O O O Flavor O.23 O.23 O.31 O.31 O.23 O.23 O.23 Tabletting aid 1.O 1.O 1.O 1.O 1.O 1.O US 8,603,440 B2 53 54 TABLE 4-continued 7. Compressed chewing gum tablet according to claim 1, wherein at least a part of the pharmaceutically active ingre Chewing gum compositions. Amounts are given in percent by weight of each composition. “granules of ex. 1 dients are adhered to at least one of bulk sweetener particles refers to the larger sized granules, while “finely grinded granules of ex. and chewing gum granules by way of flavor. 1 refers to the Smaller sized, finely grinded granules of example 1. 5 8. Compressed chewing gum tablet according to claim 1, wherein at least a part of the pharmaceutically active ingre Composition no. dients are adhered to dry-binder particles, are interspersed Components L M N O between said chewing gum granules, or are both adhered to dry-binder particles and interspersed between said chewing Layer 2 10 gum granules. GB 2, finely grinded 24.00 19.31 19.31 19.31 9. Compressed chewing gum tablet according to claim 1, granules of ex. 1 wherein at least a part of said enhancers are at least one of Bulk Sweetener 1316 9.046 9.046 8.246 interspersed between, and incorporated in, said chewing gum NPR with nicotine load 1.1 1.1 1.1 1.1 granules. 5.3% 15 Ceterizine O O O O.8 10. Compressed chewing gum tablet according to claim 1, Flavor O.230 O.304 O.304 O.304 wherein at least a part of the pH control agent is incorporated Tabletting aid 1 1 1 1 in the chewing gum granules and at least a part of the pH Layer3 control agent is part of the chewing gum composition as a GB 2, granules of ex. 1 O S.OO O O powder. Bulk Sweetener 25.50 20.40 10.2O 1016 11. Compressed chewing gum tablet according to claim 1, Polysorbate 80 O O O O.04 wherein said pharmaceutically active ingredients are at least Layer 4 partly contained within at least a part of said chewing gum GB 1, granules of ex. 1 O O S.OO S.OO granules. Bulk Sweetener O O 10.2O 10.2O 12. Compressed chewing gum tablet according to claim 1, 25 wherein at least 50% of said chewing gum granules has an Various further examples may be provided within the scope average diameter of between 100 um and 1600 um. of the invention. 13. Compressed chewing gum tablet according to claim 1, What is claimed is: wherein the chewing gum granules in the chewing gum com 1. Compressed chewing gum tablet comprising one or position comprising pharmaceutically active ingredients have more pharmaceutically active ingredients and one or more 30 average particle sizes below 1500 um. enhancers, wherein the chewing gum tablet comprises at least 14. Compressed chewing gum tablet according to claim 1, one chewing gum module comprising a chewing gum com wherein at least a part of said one or more pharmaceutically position, and wherein the chewing gum composition com active ingredients are mixed into said chewing gum mixture prises chewing gum granules containing gum base, wherein prior to granulation. said enhancers are at least partly contained within at least a 35 15. Compressed chewing gum tablet according to claim 1, part of said chewing gum granules, wherein the one or more wherein at least a part of the pharmaceutically active ingre enhancers comprise a pH control agent, wherein said pH dients are adhered to bulk sweetener particles by way of control agent facilitates that pH as measured during chewing flavor. in a mastication device is kept above the highest pKa value of 16. Compressed chewing gum tablet according to claim 1, the pharmaceutically active ingredient for at least a part of a wherein at least a part of the pharmaceutically active ingre chewing period, and wherein the one or more pharmaceuti dients are adhered to dry-binder particles. cally active ingredients comprise nicotine in the form of nico 17. Compressed chewing gum tablet according to claim 1, tine polacrilex. wherein the chewing gum composition is prepared by spray 2. Compressed chewing gum tablet according to claim 1, ing one or more flavor materials onto particles of bulk Sweet wherein said compressed chewing gum tablet comprises at 45 enerand letting particles of the pharmaceutically active ingre least two individual coherent compressed modules. dients adhere thereto. 3. Compressed chewing gum tablet according to claim 1, 18. Compressed chewing gum tablet according to claim 1, wherein the compressed chewing gum tablet comprises one wherein the chewing gum composition is prepared by spray or more gum base free modules. ing one or more flavor materials onto chewing gum granules 4. Compressed chewing gum tablet according to claim 1, 50 and particles of bulk sweetener and letting particles of the wherein the modules are layers. pharmaceutically active ingredients adhere thereto. 5. Compressed chewing gum tablet according to claim 1, 19. Compressed chewing gum tablet according to claim 1, wherein at least one of the pharmaceutically active ingredi wherein an amount of dry-binder is used to adhere active ents is separated from at least one of the enhancers by location pharmaceutical ingredients to bulk Sweetener. in different modules. 55 20. Compressed chewing gum tablet according to claim 1, 6. Compressed chewing gum tablet according to claim 1, wherein said compressed chewing gum tablet comprises at wherein at least a part of the pharmaceutically ingredients are least three individual coherent compressed modules. incorporated in at least a part of the chewing gum granules. k k k k k