(12) Patent Application Publication (10) Pub. No.: US 2016/0279056A1 Zhao Et Al

US 20160279056A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0279056A1 Zhao et al. (43) Pub. Date: Sep. 29, 2016

(54) LIQUISOFT CAPSULES Publication Classification (71) Applicant: BANNER LIFE SCIENCES LLC, (51) Int. Cl. High Point, NC (US) A6IR 9/00 (2006.01) A 6LX 9/50 (2006.01) (72) Inventors: Yinyan Zhao, Greensboro, NC (US); A63L/46.5 (2006.01) Yunhua Hu, Cary, NC (US); Mervin A6II 3L/28 (2006.01) Williams, JR., Jamestown, NC (US); A6II 45/06 (2006.01) Tatyana Dyakonov, Greensboro, NC A63L/485 (2006.01) (US); Saujanya Gosangari, Jamestown, (52) U.S. Cl. NC (US); Chue Yang, Greensboro, NC CPC ...... A61K 9/0056 (2013.01); A61K 45/06 (US); Henricus Marinus, Gerardus, (2013.01); A61K 31/485 (2013.01); A61 K Maria Van Duijnhoven, den Bosch 3 1/465 (2013.01); A61 K3I/28 (2013.01); (NL); Martin Piest, Tilburg (NL); A61K 9/5057 (2013.01); A61K 9/5052 Aqeel A Fatmi, High Point, NC (US) (2013.01); A61K 9/5089 (2013.01) (57) ABSTRACT (21) Appl. No.: 15/080,614 Described herein are oral pharmaceutical compositions Suit able for chewing, Sucking, or buccal dissolution comprising (22) Filed: Mar. 25, 2016 Soft gel capsules and liquid fills, methods for making the same, and methods for treating Subjects in need thereof with Related U.S. Application Data Such capsules. In particular, oral pharmaceutical composi (60) Provisional application No. 62/236,297, filed on Oct. tions comprising chewable. Suckable, or dissolvable soft gel 2, 2015, provisional application No. 62/138,468, filed capsules with various flowable fill compositions are on Mar. 26, 2015. described. Patent Application Publication Sep. 29, 2016 US 2016/0279056A1

FIGURE 1

120

1OO

O 2O 40 60 Time (min) US 2016/0279056A1 Sep. 29, 2016

LIQUISOFT CAPSULES properties that can be sucked or that slowly dissolve in the mouth to release pleasant-tasting or refreshing liquid fills. CROSS REFERENCE TO RELATED APPLICATIONS SUMMARY 0001. This application claims priority to U.S. Provisional 0008. One embodiment described herein is an oral phar Patent Application Nos. 62/138,468, filed on Mar. 26, 2015, maceutical composition Suitable for chewing, Sucking, or and 62/236,297, filed on Oct. 2, 2015, each of which is buccal dissolution comprising a soft capsule with a flowable incorporated herein in its entirety by express reference fill comprising one or more active pharmaceutical ingredi thereto. This application is related to International Patent ents, nutraceuticals, flavors, or refresheners. Exemplary Application No. PCT/US2016/ , filed on Mar. 25, embodiments are cough and cold over-the-counter (OTC) 2016, which is incorporated herein in its entirety by express remedies; nonsteroidal anti-inflammatory drugs (NSAIDs) reference thereto. for treating pain; nicotine satiation, nicotine-replacement therapy, or Smoking cessation therapy; breath fresheners or TECHNICAL FIELD treatments for halitosis; treatments for temporary discom forts of the stomach and gastrointestinal tract; or as a 0002. Described herein are oral pharmaceutical compo delivery means for any of the active pharmaceuticals sitions suitable for chewing. Sucking, or buccal dissolution described herein. comprising soft gel capsules and liquid fills, methods for 0009. Another embodiment described herein is an oral making the same, and methods for treating Subjects in need pharmaceutical composition Suitable for chewing, sucking, thereof with Such capsules. In particular, oral pharmaceuti or buccal dissolution comprising a shell encapsulating a cal compositions comprising chewable. Suckable, or dissolv matrix, the shell comprising: (a) one or more film-forming able softgel capsules with various flowable fill compositions polymers; (b) one or more plasticizers; (c) one or more are described. polymer modifiers; (d) one or more first Sweeteners; (e) one or more first solvents, (f) optionally, one or more excipients; BACKGROUND and a matrix comprising: (g) one or more hydrophilic 0003 Chewable dosage forms are typically manufactured vehicles: (h) one or more flavors: (i) one or more second as Solids, such as chewable tablets, or elastic semi-solids Sweeteners; () one or more second solvents; (k) one or more Such as chewing gums, molded gels, or chewable soft gelatin active pharmaceutical ingredients; and (1) optionally, one or capsules. While elastic semi-solid forms provide better more excipients. In one aspect describe herein, the film mouth feel and customer acceptance, chewable soft gelatin forming polymer comprises one or more of gelatin, partially capsules (e.g., "soft gels') have a benefit of being ingestible hydrolyzed gelatin, hydrolyzed gelatin, hydrolyzed colla and can deliver accurate amounts of active ingredients to the gen, or combinations thereof. In another aspect describe oral cavity and digestive system. herein, the plasticizer comprises one or more of glycerol, maltitol, mannitol. Xylitol, lycasin, or combinations thereof. 0004 Soft gels have gained popularity and acceptance In another aspect describe herein, the polymer modifier due to their elegant and clear gelatin shells. Furthermore, comprises one or more of citric acid, acetic acid, lactic acid, softgel capsules are uniform, stable, dissolve quickly, allow malic acid, tartaric acid, or combinations thereof. In another for liquid formulations, and are easier for most Subjects to aspect describe herein, the hydrophilic vehicle comprises swallow. propylene glycol, polyethylene glycol 400, polyvinylpyr 0005 Soft gel capsules are typically formed of a capsule rolidone K30, glycerin, sorbitol, xylitol, maltitol, or combi shell encapsulating a liquid matrix fill. Several types of soft nations thereof. In another aspect describe herein, the first gel capsules can be chewed by the user. See e.g., U.S. Pat. Sweetener comprises sucralose, aspartame, Stevia, acesul Nos. 6,258,380; 8,097,279; 8,241,665; 8,414,916; and fame potassium, Xylitol, or combinations thereof. In another 8.765,174. Such chewable soft capsules are chewed by the aspect describe herein, the flavoring comprises citric acid, subject to release the fill contents into the mouth, instead of lactic acid, sodium citrate, orange flavor, eucalyptol, pep swallowing the capsule with the fill still encapsulated within permint oil, methyl salicylate, glycine, or combinations the shell. Often the fill of chewable soft capsules contains thereof. In another aspect describe herein, the second sweet Substantial amounts of gelatin giving the fill a semi-solid ener comprises mannitol, maltitol, Xylitol, thaumatin, gly characteristic, rather than a true liquid character. cyrrhizic acid salts, acesulfame potassium, acesulfame salts, 0006 Although chewable soft capsules provide an effec Sucralose, aspartame, Stevia, or combinations thereof. In tive dosage system, user acceptance has been limited by the another aspect describe herein, the active pharmaceutical organoleptic properties of the capsules, which are some ingredient comprises one or more of astemizole, azelastine, times criticized as being leathery or rubbery. Chewable soft aZatadine, brompheniramine, carbinoxamine, cetirizine, capsules sometimes have a distinguishable difference chlorpheniramine, clemastine, cyproheptadine, deslorata between the shell and fill in terms of texture and mouth-feel. dine, dexbrompheniramine, dexchlorpheniramine, diphen Some users experience difficulty consuming the masticated hydramine, fexofenadine, hydroxy Zine, levocetirizine, lor sheath after the internal fill has been released. In addition, atadine, phenindamine, pheniramine, phenyltoloxamine, chewable soft capsules tend to harden over time. promethazine, pyrilamine, terfenadine, tripelennamine, 0007 Thus, there is an unmet need for chewable soft triprolidine, acetyl dihydrocodeine, benproperine, benzona capsule dosage forms comprising liquid fills, where the tate, benzylmorphine, bibenzonium bromide, butamirate, capsule shell can be chewed. Sucked, or that dissolves in the butorphanol, carbetapentane, chlophedianol, clobutinol, mouth and releases the active ingredient in a liquid form in clofedanol, cloperastine, codeine, dextromethorphan, dex the oral cavity. Accordingly, it is desirable to develop tromethorphan hydrobromide, diacetylmorphine, dibunate, chewable soft gelatin capsules having desirable organoleptic dihydrocodeine, dimemorfan, dimethoxanate, diphenhy US 2016/0279056A1 Sep. 29, 2016 dramine, dropropizine, droxypropine, ethylmorphine, fedri choline magnesium salicylate, diclofenac, diflunisal, etod late, glaucine, hydrocodone, hydromorphone, isoaminile, olac, etoricoxib, faislamine, fenbufen, fenoprofen, flurbipro laudanum, levodropropizine, levomethadone, levopropoxy fen, indometacin, ketoprofen, ketorolac, lornoxicam, loXo phene, meprotixol, methadone, morclofone, nepinalone, profen, meloxicam, meclofenamic acid, mefenamic acid, nicocodine, nicodicodine, normethadone, noscapine, oxela meloxicam, metamizole, methyl salicylate, magnesium din, oxolamine, pentoxyverine, pholcodine, pipaZetate, pip salicylate, nabumetone, naproxen, nimeSulide, paracetamol. eridione, prenoxdiazine, tipepidine, Zipeprol, acetylcysteine, oxyphenbutaZone, parecoxib, phenylbutaZone, piroxicam, althea root, ambroXol, antimony pentasulfide, bromhexine, salicyl salicylate, Sulindac, Sulfinpyrazone, Suprofen, tenoxi carbocisteine, cineole, combinations, combinations, creo cam, tiaprofenic acid, tolmetin, Valdecoxib, acetylsalicylic Sote, dembrexine hydrochloride, domiodol, dornase alfa, acid, aloxiprin, aminophenaZone, anilides, benorilate, ben eprazinone, erdosteine, guaiacolsulfonate, guaifenesin, hed Zomorphan derivatives, bezitramide, bucetin, buprenor erae helicis folium, ipecacuanha, letosteine, levo Verbenone, phine, butorphanol, carbasalate calcium, choline Salicylate, mannitol, mesna, neltenexine, potassium iodide, Senega, codeine, dextromoramide, dextropropoxyphene, dezocine, Sobrerol, Stepronin, tiopronin, tyloxapol, pseudoephedrine, diamorphine, diflunisal, dihydrocodeine, dihydrocodone, cetirizine, loratadine, feXofenadine, diphenhydramine, levo dihydromorphine, diphenylpropylamine derivatives, dipyro cetirizine, desloratadine, phenol, ethanol, thymol, eucalyp cetyl, ethenZamide, fentanyl, floctafenine, flupirtine, glafe tol, ethanol, methyl salicylate, chlorhexidine gluconate, nine, guacetisal, hydrocodone, hydrocodone bitartrate, cetylpyridinium chloride, hexetidine, triclosan, hydrogen hydromorphone, hydromorphone hydrochloride, imidazole peroxide, domiphen bromide, bismuth Subsalicylate, loper salicylate, ketobemidone, metamizole sodium, methadone, amide hydrochloride, aluminum hydroxide, magnesium morphinan derivatives, morphine, morphine Sulphate pen hydroxide, magnesium aluminum silicate simethicone, alu tahydrate, morphine-6-glucuronode, morpholine Salicylate, minum carbonate, calcium carbonate, sodium bicarbonate, nalbuphine, natural opium alkaloids, nefopam, nicomor hydrotalcite, magaldrate, cimetidine, famotidine, nizatidine, phine, nifenaZone, non-steroidal anti-inflammatory drugs ranitidine, lansoprazole, omeprazole, esomeprazole, rabe (NSAID), norhydrocodone, noroxycodone, opioids, opium, prazole, pantoprazole, dexlansoprazole, diphenoxylate, oripavine derivatives, oxycodeine, oxycodone, oxycodone dicyclomine, loperamide, rifaximin, alosetron, hydrochloride, oxymorphone, papaveretum, pentazocine, cholestyramine, linaclotide, lubiprostone, methylcellulose, pethidine, phenacetin, phenazocine, phenaZone, phenylpip polycarbophil, psyllium, mineral oil, glycerol, docusate eridine derivatives, piritramide, potassium salicylate, propa sodium, sodium bicarbonate, sodium phosphate, magnesium cetamol, propyphenaZone, pyrazolones, rimazolium, Salicy citrate, magnesium oxide, magnesium sulfate, bisacodyl, lamide, salicylic acid derivatives, Salsalate, sodium sennosides, Senna, castor oil, alclometasone, amcinonide, salicylate, tapentadol, tilidine, tramadol, Viminol, beclometaSone, betamethasone, budesonide, ciclesonide, Ziconotide, caffeine, taurine, ginko biloba, glucuronolac clobetasol, clobetaSone, clocortolone, cloprednol, cortiva tone, inositol, niacin, niacinamide, D-pantothenol, panax Zol, deflazacort, deoxycorticosterone, desonide desoximeta ginseng root extract, pyridoxine HCl, vitamin B12, cyano Sone, dexamethasone, diflorasone, diflucortolone, diflupred cobalamin, riboflavin, guarana, L-carnitine, Vitamin A (reti nate, fluclorolone, fludrocortisone, fludroxycortide, nol), B1 (thiamine), B2 (riboflavin), B complex, B6 (pyri flumetaSone, flunisolide, fluocinolone acetonide, fluocinon doxine), B12 (cobalamin), C (ascorbic acid), D ide, fluocortin, fluocortolone, fluorometholone, fluperolone, (cholecalciferol), E (tocopherol), F (linoleic acid), G, H fluticasone, fluticasone propionate, fluprednidene, formo (biotin), and K, and choline, folic acid, inositol, niacin, cortal, halcinonide, halometasone, hydrocortisone ace pantothenic acid, para-aminobenzoic acid, terpenoids (e.g., ponate, hydrocortisone buteprate, hydrocortisone butyrate, carotenoid terpenoids and non-carotenoid terpenoids), loteprednol, medrysone, meprednisone, methylpredniso herbal Supplements, homeopathic Supplements, glandular lone, methylprednisolone aceponate, mometasone furoate, Supplements, polyphenolics, flavonoid polyphenolics, phe paramethasone, prednicarbate, prednisone, prednisolone, nolic acids, curcumin, resveratrol, lignans, glucosinolates, prednylidene, rimexolone, tiXocortol, triamcinolone, ulo isothiocyanates, indoles, thiosulfinates, phytosterols, anthra betasol, 5-fluorouracil, 5-fluorodeoxyuridine, capecitabine, quinones, capsaicin, piperine, chlorophyll, betaine, Oxalic calcium Supplements, calcimimetics, cinacalcet, nicotine, acid, acetyl-L-carnitine, allantoin, androstenediol, andros nicotine polacrilex, bupropion, Varenicline, disulfiram, cal tendione, betaine (trimethylglycine), caffeine, calcium pyru cium carbimide, acamprosate, naltrexone, buprenorphine, vate (pyruvic acid), carnitine, carnosine, carotene, carote methadone, levacetylmethadol, lofexidine, betahistine, cin noid, choline, chlorogenic acid, cholic acid, chondroitin narizine, flunarizine, acetylleucine, gangliosides, ganglio Sulfate, chondroitin Sulfate, cholestan, chrysin, coenzyme side derivatives, tirilazad, riluzole, xaliproden, hydroxybu Q10, conjugated linoleic acid, corosolic acid, creatine, dehy tyric acid, amifampiridine, doxylamine, diphenhydramine droepiandrosterone, dichlorophen, diindolymethane, dim hydrochloride, melatonin, 1-theanine, monofluorophos ethylglycine, dimercapto Succinic acid, ebselen, ellagic acid, phate, lactoferrin, lysozyme, lactoperoxidase, glucose oxi enzymes, fisetin, formononetin, glucaric acid (glucarate), dase, mutanase, dextranase, glycerol, carbamide peroxide, glucosamine (HCl or Sulfate), glucosamine (N-acetyl), glu Sodium bicarbonate, hydrated silica, silicon dioxide, poly tathione, hesperidine, hydroxy-3-methylbutyric acid, 5-hy vinylpyrrolidone, potassium nitrate, sodium monofluoro droxytryptophan, indole-3-carbinol, inositol, isothiocya phosphate, Sodium tripolyphosphate, strontium chloride, nates, linolenic acid-gamma, lipoic acid (alpha), melatonin, potassium nitrate, strontium acetate, strontium chloride, methylsulfonylmethane, menthol, minerals, naringin, pan calcium sodium phosphosilicate, benzocaine, lidocaine, creatin, para-aminobenzoic acid, paraben (methyl or pro clove oil, Sodium bicarbonate, citric acid, tartaric acid, pyl), phenolics, phosphatidylcholine, phosphatidylserine, aspirin, ibuprofen, aceclofenac, acemetacin, aloxiprin, phospholipids, phytosterols, progesterone, pregnenolone, aZapropaZone, benorilate, bromfenac, carprofen, celecoxib, omega-3 fatty acids, quercetin, resveratrol, D-ribose, rutin, US 2016/0279056A1 Sep. 29, 2016

S-adenosylmethionine, salicylic acid, Sulforaphane, tartaric congestion, nasal congestion, sinusitis, throat or bronchial acid, taxifolin, tetrahydropalmatine, theophyline, theobro irritation, allergies, fever, flu, inflammation of the gastroin mine, tigogenin, troXerutin, tryptophan, tocotrienol (alpha, testinal tract, Sour stomach, neoplasia, hyperthyroidism, beta, and gamma), Zeaxanthin, gingko biloba, ginger, cats hypercalcemia, hyperparathyroidism, parathyroid carci claw, hypericum, aloe Vera, evening primrose, garlic, gin noma, indigestion, heartburn, irritable bowels, constipation, Seng, capsicum, dong quai, ginseng, feverfew, fenugreek, diarrhea, insomnia, dry mouth, mouth odor, halitosis, stained echinacea, green tea, marshmallow, saw palmetto, tea tree teeth, oral pain, loss of enamel, nicotine desire; cessation of oil, fish oil, psyllium, kava-kava, licorice root, mahonia urge to Smoke, fatigue, or malaise comprising administering aquifolium, hawthorne, tumeric, witch Hazel, yohimbe, to a subject in need thereof any of the oral pharmaceutical aleurain, mistletoe, bilberry, bee pollen, peppermint oil, compositions described herein. beta-carotene, genistein, lutein, lycopene, polyphenols, Bifi 0012 Another embodiment described herein is a phar dobacterium infantis 35624, Bifidobacterium lactis HNO19, maceutical composition comprising a soft dosage form Lactobacillus reuteri ATCC55730, Lactobacillus rhamno comprising a shell encapsulating a liquid matrix, wherein sus, Lactobacillus casei DN-114 001, Bifidobacterium lactis the shell comprises: (a) about 20% to about 60% of one or Bb-12, or mixtures or combinations thereof. In another more film-forming polymers; (b) about 30% to about 70% of aspect describe herein, the excipients comprise one or more one or more plasticizers; (c) about 0.5% to about 2% of one flavorings, colorings, hygroscopic polymers, opacifiers, or more polymer modifiers; (d) about 0.1% to about 5% of thickening agents, Surfactants, or pharmaceutically accept one or more first Sweeteners; (e) about 10% to about 40% of able excipients. In another aspect describe herein, the one or one or more solvents; and the matrix comprises: (f) about more active pharmaceutical ingredients comprises one or 30% to about 95% of one or more hydrophilic vehicles; (g) more of dextromethorphan hydrobromide, menthol, thymol, about 0.05% to about 5% of one or more second Sweeteners; nicotine, nicotine polacrilex, bismuth Subsalicylate, (h) about 0.01% to about 6% of one or more flavors: (i) NSAIDS, or combinations thereof. In another aspect about 1% to about 20% water; and () about 0.05% to about describe herein, the matrix is a liquid, flowable gel, or 60% of one or more active pharmaceutical ingredients. Viscous semi-solid. In another aspect describe herein, the 0013 Another embodiment described herein is a method shell comprises: (a) about 20% to about 60% of one or more of delivering an active pharmaceutical ingredient to a patient film-forming polymers; (b) about 30% to about 70% of one population unable to receive a conventional dosage form or more plasticizers; (c) about 0.5% to about 2% of one or comprising administering to the patient the oral pharmaceu more polymer modifiers; (d) about 0.1% to about 5% of one tical composition comprising a soft dosage form as or more first sweeteners; and (e) about 10% to about 40% of described herein. one or more solvents. In another aspect describe herein, the 0014) Another embodiment described herein is a compo matrix comprises: (a) about 30% to about 95% of one or sition for delivering an active pharmaceutical ingredient to more hydrophilic vehicles; (b) about 0.05% to about 5% of a patient population unable to receive a conventional dosage one or more second sweeteners; (c) about 0.01% to about form comprising administering to the patient in need thereof 6% of one or more flavors; (d) about 1% to about 20% one an oral pharmaceutical composition comprising a soft dos or more solvents; and (e) about 0.05% to about 60% of one age form as described herein. or more active pharmaceutical ingredients. In another aspect 0015. Another embodiment described herein is a phar describe herein, the shell comprises: (a) about 35% of one or maceutical combination comprising any of the compositions more film-forming polymers; (b) about 37% of one or more described herein and one or more additional therapeutic plasticizers; (c) about 0.5% of one or more polymer modi compounds. In one aspect describe herein, the one or more fiers; (d) about 2.7% of one or more first sweeteners; and (e) additional therapeutic compounds comprises one or more of about 21% of one or more solvents. In another aspect NSAIDS, diphenhydramine, codeine, chlorhexidine, cime describe herein, the ratio of the active pharmaceutical ingre tidine, ranitidine, famotidine, ondansetron, omeprazole, lan dient to a combined weight percentage of the hydrophilic soprazole, rabeprazole, esomeprazole, pantoprazole, cal vehicle, flavor, Sweetener, Solvent and excipient is about cium Supplements, magnesium hydroxide, bupropion, or 1:0.5 to about 1:500. Varenicline. 0010. Another embodiment described herein is method 0016. Another embodiment described herein is a method for treating, retarding the progression of prophylaxis of for treating for treating, retarding the progression of pro delaying the onset of ameliorating, reducing the symptoms phylaxis of delaying the onset of ameliorating, reducing the of or promoting health, including but not limited to of one symptoms of or promoting health, including but not limited or more of pain, inflammation, cough, cold, sinusitis, throat to of one or more of pain, inflammation, cough, cold, chest or bronchial irritation, fever, flu, inflammation of the gas congestion, nasal congestion, sinusitis, throat or bronchial trointestinal tract, neoplasia, hyperthyroidism, hypercalce irritation, allergies, fever, flu, inflammation of the gastroin mia, hyperparathyroidism, parathyroid carcinoma, indiges testinal tract, Sour stomach, neoplasia, hyperthyroidism, tion, heartburn, irritable bowels, constipation, diarrhea, hypercalcemia, hyperparathyroidism, parathyroid carci insomnia, dry mouth, halitosis, stained teeth, oral pain, loss noma, indigestion, heartburn, irritable bowels, constipation, of enamel, cessation of urge to Smoke, fatigue, or malaise diarrhea, insomnia, dry mouth, mouth odor, halitosis, stained comprising administering to a subject in need thereof any of teeth, oral pain, loss of enamel, nicotine desire; cessation of the oral pharmaceutical compositions described herein. urge to Smoke, fatigue, or malaise comprising administering 0011. Another embodiment described herein is a compo to a Subject in need thereof any of the pharmaceutical sition for treating, retarding the progression of prophylaxis combinations described herein. of delaying the onset of ameliorating, reducing the Symp 0017. Another embodiment described herein is a method toms of, or promoting health, including but not limited to of for manufacturing an oral pharmaceutical composition com one or more of pain, inflammation, cough, cold, chest prising the steps of: (a) preparing a gel mass composition US 2016/0279056A1 Sep. 29, 2016 where the composition comprises one or more film forming ene glycol 400, polyvinylpyrrolidone K30, glycerin, sorbi polymers, one or more plasticizers, one or more Sweeteners, tol, xylitol, maltitol, or combinations thereof. In another one or more excipients in one or more solvents; (b) mixing aspect described herein, the first Sweetener comprises the first solution at least about 50° C. under vacuum for 1 to Sucralose, aspartame, Stevia, acesulfame potassium, Xylitol, 2 hours; (c) preparing a gel fill composition comprising one or combinations thereof. In another aspect described herein, or more hydrophilic vehicles, one or more flavors, one or the flavoring comprises citric acid, lactic acid, sodium more Sweeteners, one or more excipients, one or more active citrate, orange flavor, menthol, eucalyptol, peppermint oil, pharmaceutical ingredients in one or more solvents; (d) methyl salicylate, glycine, or combinations thereof. In mixing the second solution at least about 50° C.; (e) casting the gel composition into films or ribbons using heat-con another aspect described herein, the second Sweetener com trolled drums or Surfaces; and (f) forming a soft dosage form prises mannitol, maltitol, Xylitol, thaumatin, glycyrrhizic comprising a liquid matrix fill using rotary die encapsulation acid salts, acesulfame potassium, acesulfame salts, sucral technology. ose, aspartame, Stevia, or combinations thereof. In another aspect described herein, the excipients comprise one or more 0.018. Another embodiment described herein is an oral flavorings, colorings, hygroscopic polymers, opacifiers, pharmaceutical composition comprising a soft dosage form thickening agents, Surfactants, or pharmaceutically accept comprising an active pharmaceutical ingredient in a liquid able excipients. In another aspect described herein, the matrix produced by any of the methods described herein. In matrix is a liquid, flowable gel, or viscous semi-solid. In one aspect described herein, the dosage form is stable for at another aspect described herein, the shell comprises: (a) 25° C. for at least one year. about 10% to about 80% of one or more film-forming 0019. Another embodiment described herein is a kit for polymers; (b) about 20% to about 70% of one or more dispensing any of the oral pharmaceutical compositions plasticizers; (c) about 0.01% to about 5% of one or more described herein comprising: (a) at least one oral pharma polymer modifiers; (d) about 0.1% to about 5% of one or ceutical composition; (b) at least one moisture proof dis more first sweeteners; (e) about 5% to about 50% of one or pensing receptacle comprising blister or strip packs, an more first solvents, (f) optionally, one or more excipients; aluminum blister, a transparent or opaque polymer blister and the matrix comprises: (g) about 40% to about 99% of with pouch, polypropylene tubes, colored blister materials, one or more hydrophilic vehicles: (h) about 0.5% to about tubes, bottles, and bottles optionally containing a child 10% of one or more flavors: (i) about 0.5% to about 5% of resistant feature, optionally comprising a desiccant. Such as one or more second sweeteners; () about 1% to about 20% a molecular sieve or silica gel; and optionally (c) at least one of one or more second solvents; (k) about 0.1% to about 5% daily regimen for the oral pharmaceutical composition; and of dextromethorphan hydrobromide: (1) about 0.05% to (d) an insert comprising instructions or prescribing infor about 1% of menthol; and (m) optionally, one or more mation for the oral pharmaceutical composition. In one excipients. In another aspect described herein, the shell aspect described herein, the kit is useful for treating pain, comprises: (a) about 10% to about 50% gelatin, 150 Bloom: inflammation, cough, cold, chest congestion, nasal conges (b) about 1% to about 20% gelatin, 100 Bloom; (c) about 1% tion, sinusitis, throat or bronchial irritation, allergies, fever, to about 10% hydrolyzed collagen; (d) about 10% to about flu, inflammation of the gastrointestinal tract, Sour stomach, 20% lycasin; (e) about 10% to about 50% glycerin; (f) about neoplasia, hyperthyroidism, hypercalcemia, hyperparathy 0.1% to about 2% citric acid; (g) about 0.1% to about 5% roidism, parathyroid carcinoma, indigestion, heartburn, irri xylitol: (h) about 0.1% to about 1% sucralose; and (i) about table bowels, constipation, diarrhea, insomnia, dry mouth, 10% to about 50% water. In another aspect described herein, mouth odor, halitosis, stained teeth, oral pain, loss of the matrix comprises: (a) about 10% to about 40% polyeth enamel, nicotine desire; cessation of urge to Smoke, fatigue, ylene glycol 400; (b) about 1% to about 15% propylene or malaise according to any of the methods described herein. glycol; (c) about 0.1% to about 5% polyvinylpyrrolidone 0020. Another embodiment described herein is an oral K30; (d) about 25% to about 75% lycasin; (e) about 0.1% to pharmaceutical composition Suitable for chewing, Sucking, about 5% citric acid: (f) about 0.1% to about 5% lactic acid; or buccal dissolution comprising a shell encapsulating a (g) about 0.1% to about 5% sucralose: (h) about 0.1% to matrix, the shell comprising: (a) one or more film-forming about 5% acesulfame potassium: (i) about 1% to about 10% polymers; (b) one or more plasticizers; (c) one or more water; () about 0.1% to about 5% dextromethorphan hyd polymer modifiers; (d) one or more first Sweeteners; (e) one robromide; and (k) about 0.05% to about 1% menthol. In or more first solvents; and (f) optionally, one or more another aspect described herein, the shell comprises: (a) excipients; and the matrix comprising: (g) one or more about 20% gelatin, 150 Bloom; (b) about 9% gelatin, 100 hydrophilic vehicles: (h) one or more flavors: (i) one or more Bloom; (c) about 5% hydrolyzed collagen; (d) about 17% second Sweeteners; () one or more second solvents; (k) lycasin; (e) about 25% glycerin; (f) about 0.5% citric acid; dextromethorphan hydrobromide: (1) menthol; and (m) (g) about 2.5% about xylitol: (h) about 0.2% sucralose; and optionally, one or more excipients. In one aspect described (i) about 21% water; and the matrix comprises: (i) about herein, the film-forming polymer comprises one or more of 21% polyethylene glycol 500; (k) about 8% propylene gelatin, partially hydrolyzed gelatin, hydrolyzed gelatin, glycol: (1) about 1% polyvinylpyrrolidone K30; (m) about hydrolyzed collagen, or combinations thereof. In another 58% lycasin; (n) about 1% citric acid; (o) about 1% lactic aspect described herein, the plasticizer comprises one or acid; (p) about 0.6% sucralose; (q) about 0.6% acesulfame more of glycerol, maltitol, mannitol. Xylitol, lycasin, or potassium; (r) about 5% water: (s) about 1% dextrometho combinations thereof. In another aspect described herein, the rphan hydrobromide; and (t) about 0.1% menthol. In another polymer modifier comprises one or more of citric acid, aspect described herein, the ratio of the active pharmaceu acetic acid, lactic acid, malic acid, tartaric acid, or combi tical ingredient to a combined weight percentage of the nations thereof. In another aspect described herein, the hydrophilic vehicle, flavor, sweetener, solvent and excipient hydrophilic vehicle comprises propylene glycol, polyethyl is about 1:50 to about 1:200. US 2016/0279056A1 Sep. 29, 2016

0021. Another embodiment described herein is a method 0028. Another embodiment described herein is a phar for treating, retarding the progression of prophylaxis of maceutical dosage form for treating one or more of inflam delaying the onset of ameliorating, or reducing the Symp mation, cough, cold, chest congestion, nasal congestion, toms of, or promoting health, including but not limited to of sinusitis, throat or bronchial irritation, flu, fever, or pain one or more of inflammation, cough, cold, chest congestion, comprising any of the pharmaceutical compositions nasal congestion, sinusitis, throat or bronchial irritation, flu, described herein. fever, or pain comprising administering to a subject in need 0029. Another embodiment described herein is a method thereof any of the oral pharmaceutical compositions for treating inflammation, cough, cold, chest congestion, described herein. nasal congestion, sinusitis, throat or bronchial irritation, flu, 0022. Another embodiment described herein is a compo fever, or pain comprising administering one or more dosage sition for treating, retarding the progression of prophylaxis forms comprising any of the pharmaceutical compositions of delaying the onset of ameliorating, reducing the Symp described herein. toms of, or promoting health, including but not limited to of 0030. Another embodiment described herein is a means one or more of inflammation, cough, cold, chest congestion, for treating inflammation, cough, cold, chest congestion, nasal congestion, sinusitis, throat or bronchial irritation, flu, nasal congestion, sinusitis, throat or bronchial irritation, flu, fever, or pain comprising administering to a subject in need fever, or pain comprising administering one or more dosage thereof any of the oral pharmaceutical compositions forms comprising any of the pharmaceutical compositions described herein. described herein. 0023. Another embodiment described herein is a phar 0031. Another embodiment described herein is a method maceutical composition comprising a soft dosage form for manufacturing the oral pharmaceutical composition comprising a shell encapsulating a liquid matrix, wherein comprising the steps of: (a) preparing a gel fill composition the shell comprises: (a) about 10% to about 50% gelatin, 150 comprising a first solution and a second solution wherein: (i) Bloom; (b) about 1% to about 20% gelatin, 100 Bloom; (c) the first solution comprises polyvinylpyrrolidone K30, about 1% to about 10% hydrolyzed collagen; (d) about 10% orange flavor, citric acid, Sucralose, acesulfame potassium, to about 20% lycasin; (e) about 10% to about 50% glycerin; lycasin and water, one or more excipients in one or more (f) about 0.1% to about 2% citric acid; (g) about 0.1% to solvents and mixed at a temperature no greater than 55° C. about 5% xylitol: (h) about 0.1% to about 1% sucralose; and until dissolved and clear; (ii) the second solution comprises (i) about 10% to about 50% water; and the matrix comprises: polyethylene glycol 400, propylene glycol and lactic acid (j) about 10% to about 40% polyethylene glycol 400; (k) and mixed until dissolved and clear; where the composition about 1% to about 15% propylene glycol: (1) about 0.1% to comprises one or more film forming polymers, one or more about 5% polyvinylpyrrolidone K30; (m) about 25% to plasticizers, one or more Sweeteners, one or more excipients about 75% lycasin; (n) about 0.1% to about 5% citric acid; in one or more solvents; (iii) adding dextromethorphan (o) about 0.1% to about 5% lactic acid; (p) about 0.1% to hydrobromide and menthol to the second solution and about 5% sucralose; (q) about 0.1% to about 5% acesulfame mixing the first Solution and heating to no greater than 55° potassium; (r) about 1% to about 10% water: (s) about 0.1% C. until dissolved; and (iv) combining the first solution with to about 5% dextromethorphan hydrobromide; and (t) about the second solution and purging with nitrogen; (b) preparing 0.05% to about 1% menthol. a gel mass composition comprising one or more film form ing polymers, one or more plasticizers, one or more Sweet 0024. Another embodiment described herein is a method eners, one or more excipients and one or more solvents; (c) of delivering an active pharmaceutical ingredient to a patient casting the gel composition into films or ribbons using population unable to receive a conventional dosage form heat-controlled drums or Surfaces; and (d) forming a soft comprising administering to the patient any of the oral dosage form comprising a liquid matrix fill using rotary die pharmaceutical compositions described herein. encapsulation technology. 0025. Another embodiment described herein is a compo sition for delivering an active pharmaceutical ingredient to 0032. Another embodiment described herein is a soft a patient population unable to receive a conventional dosage dosage form comprising an active pharmaceutical ingredient form comprising administering to the patient in need thereof in a liquid matrix produced by any of the methods described any of the oral pharmaceutical compositions described herein. In one aspect described herein, the dosage form is herein. stable for at least 1 year at 25° C. 0033. Another embodiment described herein is an oral 0026. Another embodiment described herein is a phar pharmaceutical composition Suitable for chewing, sucking, maceutical combination comprising any one of the compo or buccal dissolution comprising a shell encapsulating a sitions described herein and one or more additional thera matrix, the shell comprising: (a) one or more film-forming peutic compounds. In one aspect described herein, the one or polymers; (b) one or more plasticizers; (c) one or more more additional therapeutic compound comprises one or polymer modifiers; (d) one or more first Sweeteners; (e) one more of NSAIDS, diphenhydramine, or codeine. or more first solvents; and (f) optionally, one or more 0027. Another embodiment described herein is a method excipients; and the matrix comprising: (g) one or more for treating for treating, retarding the progression of pro hydrophilic vehicles: (h) one or more flavors: (i) one or more phylaxis of delaying the onset of ameliorating, reducing the second Sweeteners; () one or more second solvents; (k) symptoms of or promoting health, including but not limited thymol: (1) menthol; and (m) optionally, one or more excipi to of one or more of inflammation, cough, cold, chest ents. In one aspect described herein, the film-forming poly congestion, nasal congestion, sinusitis, throat or bronchial mer comprises one or more of gelatin, partially hydrolyzed irritation, flu, fever, or pain comprising administering to a gelatin, hydrolyzed gelatin, hydrolyzed collagen, or combi Subject in need thereof any of the pharmaceutical combina nations thereof. In another aspect described herein, the tions described herein. plasticizer comprises one or more of glycerol, maltitol, US 2016/0279056A1 Sep. 29, 2016 mannitol. Xylitol, lycasin, or combinations thereof. In ingredient to a combined weight percentage of the hydro another actic acid, malic acid, tartaric acid, or combinations philic vehicle, flavor, Sweetener, solvent and excipient is thereof. In another aspect described herein, the hydrophilic about 1:250 to about 1:1000. vehicle comprises propylene glycol, polyethylene glycol 0034. Another embodiment described herein is a method 400, polyvinylpyrrolidone K30, glycerin, sorbitol, xylitol, for treating, retarding the progression of prophylaxis of maltitol, or combinations thereof. In another aspect delaying the onset of ameliorating, or reducing the Symp described herein, the first Sweetener comprises Sucralose, toms of, or promoting health, including but not limited to of aspartame, Stevia, acesulfame potassium, Xylitol, or combi one or more of dry mouth, halitosis, stained teeth, oral pain, nations thereof. In another aspect described herein, the loss of enamel, refreshing breath, inhibiting onset of breath flavoring comprises citric acid, lactic acid, sodium citrate, malodor, or freshening the oral cavity comprising adminis orange flavor, eucalyptol, peppermint oil, methyl salicylate, tering to a subject in need thereof any of the oral pharma glycine, or combinations thereof. In another aspect ceutical compositions described herein. described herein, the second Sweetener comprises mannitol, 0035 Another embodiment described herein is a compo maltitol. Xylitol, thaumatin, glycyrrhizic acid salts, acesul sition for treating, retarding the progression of prophylaxis fame potassium, acesulfame salts, sucralose, aspartame, of delaying the onset of ameliorating, reducing the Symp Stevia, or combinations thereof. In another aspect described toms of, or promoting health, including but not limited to of herein, the excipients comprise one or more flavorings, one or more of dry mouth, halitosis, stained teeth, oral pain, colorings, hygroscopic polymers, opacifiers, thickening loss of enamel, refreshing breath, inhibiting onset of breath agents, Surfactants, or pharmaceutically acceptable excipi malodor, or freshening the oral cavity comprising adminis ents. In another aspect described herein, the matrix is a tering to a subject in need thereof any of the oral pharma liquid, flowable gel, or viscous semi-solid. In another aspect ceutical compositions described herein. described herein, the shell comprises: (a) about 10% to about 0036) Another embodiment described herein is a phar 80% of one or more film-forming polymers; (b) about 20% maceutical composition comprising a soft dosage form to about 70% of one or more plasticizers; (c) about 0.01% comprising a shell encapsulating a liquid matrix, wherein to about 5% of one or more polymer modifiers; (d) about the shell comprises: (a) about 10% to about 40% gelatin, 100 0.1% to about 5% of one or more first Sweeteners; (e) about Bloom; (b) about 1% to about 10% hydrolyzed collagen; (c) 5% to about 50% of one or more first solvents; and (f) about 10% to about 30% lycasin; (d) about 10% to about optionally, one or more excipients; and the matrix com 40% glycerin; (e) about 1% to about 10% propylene glycol; prises: (g) about 50% to about 99% of one or more hydro (f) about 0.05% to about 2% citric acid; (g) about 1% to philic vehicles: (h) about 0.01% to about 5% of one or more about 5% xylitol: (h) about 0.05% to about 2% sucralose: (i) flavors: (i) about 0.01% to about 5% of one or more second about 0.05% to about 2% peppermint oil; and () about 10% sweeteners; () about 1% to about 20% of one or more to about 40% water; and the matrix comprises: (k) about second solvents; (k) about 0.001% to about 1% of thymol; 30% to about 60% glycerin: (1) about 0.05% to about 5% (1) about 0.05% to about 1% of menthol; and (m) optionally, propylene glycol; (m) about 0.1% to about 5% polyvinylpyr one or more excipients. In another aspect described herein, rolidone K30; (n) about 20% to about 60% sorbitol; (o) the shell comprises: (a) about 10% to about 40% gelatin, 100 about 0.1% to about 5% citric acid; (p) about 0.1% to about Bloom; (b) about 1% to about 10% hydrolyzed collagen; (c) 5% sucralose; (q) about 0.025% to about 2% eucalyptol; (r) about 10% to about 30% lycasin; (d) about 10% to about about 0.05% to about 2% peppermint oil: (s) about 1% to 40% glycerin; (e) about 1% to about 10% propylene glycol; about 20% water, (t) about 0.001% to about 0.01% thymol; (f) about 0.05% to about 2% citric acid; (g) about 1% to and (u) about 0.05% to about 3% menthol. about 5% xylitol: (h) about 0.05% to about 2% sucralose: (i) 0037. Another embodiment described herein is a method about 0.05% to about 2% peppermint oil; and () about 10% of delivering an active pharmaceutical ingredient to a patient to about 40% water. In another aspect described herein, the population unable to receive a conventional dosage form matrix comprises: (a) about 30% to about 60% glycerin; (b) comprising administering to the patient the oral pharmaceu about 0.05% to about 5% propylene glycol; (c) about 0.1% tical composition comprising any of the soft dosage forms to about 5% polyvinylpyrrolidone K30; (d) about 20% to described herein. about 60% sorbitol; (e) about 0.1% to about 5% citric acid; 0038 Another embodiment described herein is a compo (f) about 0.1% to about 5% sucralose: (g) about 0.025% to sition for delivering an active pharmaceutical ingredient to about 2% eucalyptol: (h) about 0.05% to about 2% pepper a patient population unable to receive a conventional dosage mint oil: (i) about 1% to about 20% water: (i) about 0.001% form comprising administering to the patient in need thereof to about 0.01% thymol; and (k) about 0.05% to about 3% an oral pharmaceutical composition comprising any of the menthol. In another aspect described herein, the shell com Soft dosage forms described herein. prises: (a) about 27% gelatin, 100 Bloom; (b) about 5% 0039. Another embodiment described herein is a phar hydrolyzed collagen; (c) about 17% lycasin; (e) about 21% maceutical combination comprising any one of the compo glycerin; (f) about 1% propylene glycol: (g) about 0.5% sitions described herein and one or more additional thera citric acid; (h) about 2.5% xylitol: (i) about 0.8% sucralose; peutic compounds. In one aspect described herein, the one or (j) about 0.1% peppermint oil; (k) about 24% water; and the more additional therapeutic compounds comprises chlo matrix comprises: (1) about 42% glycerin; (m) about 2% rhexidine or ethanol. propylene glycol; (n) about 3% polyvinylpyrrolidone K30; 0040 Another embodiment described herein is a method (o) about 40% sorbitol: (p) about 0.3% citric acid; (q) about for treating for treating, retarding the progression of pro 0.5% sucralose: (r) about 0.1% eucalyptol: (s) about 0.3% phylaxis of delaying the onset of ameliorating, reducing the peppermint oil, (t) about 10% water; (u) about 0.004% symptoms of or promoting health, including but not limited thymol; and (v) about 0.2% menthol. In another aspect to of one or more of dry mouth, halitosis, stained teeth, oral described herein, the ratio of the active pharmaceutical pain, loss of enamel, refreshing breath, inhibiting onset of US 2016/0279056A1 Sep. 29, 2016 breath malodor, or freshening the oral cavity comprising K30, glycerin, sorbitol, xylitol, maltitol, or combinations administering to a subject in need thereof any of the phar thereof. In one aspect described herein, the first sweetener maceutical combinations described herein. comprises Sucralose, aspartame, Stevia, acesulfame potas 0041 Another embodiment described herein is a phar sium, Xylitol, or combinations thereof. In one aspect maceutical dosage form for refreshing breath, inhibiting described herein, the flavoring comprises citric acid, lactic onset of breath malodor, treating halitosis, or freshening the acid, sodium citrate, orange flavor, eucalyptol, peppermint oral cavity comprising any of the pharmaceutical composi oil, methyl salicylate, glycine, or combinations thereof. In tions described herein. one aspect described herein, the second Sweetener comprises 0.042 Another embodiment described herein is a method mannitol, maltitol. Xylitol, thaumatin, glycyrrhizic acid salts, for refreshing breath, inhibiting onset of breath malodor, acesulfame potassium, acesulfame salts, Sucralose, aspar treating halitosis, or freshening the oral cavity comprising tame, Stevia, or combinations thereof. In one aspect administering one or more dosage forms comprising any of described herein, the excipients comprise one or more the pharmaceutical compositions described herein. flavorings, colorings, hygroscopic polymers, opacifiers, 0.043 Another embodiment described herein is a means thickening agents, Surfactants, or pharmaceutically accept for refreshing breath, inhibiting onset of breath malodor, able excipients. In one aspect described herein, the matrix is treating halitosis, or freshening the oral cavity comprising a liquid, flowable gel, or viscous semi-solid. In one aspect administering one or more dosage forms comprising any of described herein, the shell comprises: (a) about 20% to about the pharmaceutical compositions described herein. 80% of one or more film-forming polymers; (b) about 20% 0044 Another embodiment described herein is a method to about 70% of one or more plasticizers; (c) about 0.01% for manufacturing an oral pharmaceutical composition com to about 5% of one or more polymer modifiers; (d) about prising the steps of: (a) preparing a gel fill composition 0.1% to about 5% of one or more first sweeteners; (e) about comprising a first gel fill solution and a second gel fill 5% to about 50% of one or more first solvents: (f) optionally, Solution, wherein (i) the first gel fil Solution comprises one one or more excipients; and the matrix comprises: (g) about or more hydrophilic vehicle, sweetener, flavor, thymol, in 30% to about 80% of one or more hydrophilic vehicles: (h) one or more solvents and is mixed at a temperature between about 0.5% to about 10% of one or more flavors: (i) about 30-50° C. until dissolved; (ii) the second gel fill solution 0.01% to about 5% of one or more second sweeteners; () comprises one or more hydrophilic vehicles and menthol about 1% to about 30% of one or more second solvents; (k) and is mixed at a temperature between 30-50° C. until about 0.1% to about 5% of nicotine polacrilex; and (m) dissolved; and (iv) combining the first gel fill solution and optionally, one or more excipients. In one aspect described the second gel fill solution, adding flavor and mixing for at herein, the shell comprises: (a) about 10% to about 40% least 25 minutes; (b) preparing a gel mass composition gelatin, 150 Bloom; (b) about 1% to about 20% gelatin, 100 comprising one or more film forming polymers, one or more Bloom; (c) about 1% to about 10% gelatin hydrolysate; (d) plasticizers, one or more Sweeteners, one or more excipients about 10% to about 40% glycerin; (e) about 10% to about and one or more solvents; (c) casting the gel composition 40% maltitol: (f) about 0.05% to about 2% citric acid; (g) into films or ribbons using heat-controlled drums or Sur about 1% to about 5% xylitol: (h) about 0.05% to about 2% faces; and (d) forming a soft dosage form comprising a sucralose: (i) about 0.05% to about 2% peppermint oil; and liquid matrix fill using rotary die encapsulation technology. () about 10% to about 40% water. In another aspect 0.045 Another embodiment described herein is a soft described herein, the matrix comprises: (a) about 0.05% to dosage form comprising an active pharmaceutical ingredient about 5% polyethylene glycol 400; (b) about 10% to about in a liquid matrix produced by any of the methods described 40% glycerin; (c) about 0.1% to about 5% xylitol; (d) about herein. In one aspect described herein, the dosage form is 10% to about 60% maltitol; (e) about 0.1% to about 10% stable for at least 1 year at 25° C. glycine; (f) about 0.1% to about 5% sucralose; (g) about 0046. Another embodiment described herein is an oral 0.025% to about 2% menthol: (h) about 0.025% to about 2% pharmaceutical composition Suitable for chewing, Sucking, peppermint oil: (i) about 1% to about 30% water; and () or buccal dissolution comprising a shell encapsulating a about 0.01% to about 5% nicotine polacrilex. In another matrix, the shell comprising: (a) one or more film-forming aspect described herein, the shell comprises: (a) about 22% polymers; (b) one or more plasticizers; (c) one or more gelatin, 150 Bloom; (b) about 10% gelatin, 100 Bloom; (c) polymer modifiers; (d) one or more first Sweeteners; (e) one about 5% gelatin hydrolysate; (d) about 20% glycerin; (e) or more first solvents; and (f) optionally, one or more about 17% maltitol: (f) about 0.5% citric acid; (g) about excipients; and the matrix comprising: (g) one or more 2.6% xylitol: (h) about 0.2% sucralose: (i) about 0.3% hydrophilic vehicles: (h) one or more flavors: (i) one or more peppermint oil; and () about 21% water; and the matrix second Sweeteners; () one or more second solvents; (k) comprises: (k) about 1% polyethylene glycol 400: (1) about nicotine polacrilex, and (1) optionally, one or more excipi 19% glycerin; (m) about 3% xylitol; (n) about 37% maltitol; ents. In one aspect described herein, the film-forming poly (o) about 5% glycine; (p) about 0.2% sucralose; (q) about mer comprises one or more of gelatin, partially hydrolyzed 0.04% menthol; (r) about 0.04% peppermint oil: (s) about gelatin, hydrolyzed gelatin, hydrolyzed collagen, or combi 17% water; and (t) about 2% nicotine polacrilex. In another nations thereof. In another aspect described herein, the aspect described herein, the ratio of the active pharmaceu plasticizer comprises one or more of glycerol, maltitol, tical ingredient to a combined weight percentage of the mannitol. Xylitol, lycasin, or combinations thereof. In one hydrophilic vehicle, flavor, sweetener, solvent and excipient aspect described herein, the polymer modifier comprises one is about 1:10 to about 1:100. or more of citric acid, acetic acid, lactic acid, malic acid, 0047 Another embodiment described herein is a method tartaric acid, or combinations thereof. In one aspect for treating, retarding the progression of prophylaxis of described herein, the hydrophilic vehicle comprises propyl delaying the onset of ameliorating, or reducing the Symp ene glycol, polyethylene glycol 400, polyvinylpyrrolidone toms of, or promoting health, including but not limited to US 2016/0279056A1 Sep. 29, 2016

cessation of urge to Smoke, satiating nicotine desire, nico or more dosage forms comprising any of the pharmaceutical tine-replacement therapy, or Smoking cessation therapy compositions described herein. comprising administering to a subject in need thereof any of 0056. Another embodiment described herein is a means the oral pharmaceutical compositions described herein. for satiating nicotine desire, nicotine-replacement therapy, 0048. Another embodiment described herein is a compo or Smoking cessation therapy comprising administering one sition for treating, retarding the progression of prophylaxis or more dosage forms comprising any of the pharmaceutical of delaying the onset of ameliorating, reducing the Symp compositions described herein. toms of, or promoting health, including but not limited to 0057 Another embodiment described herein is a method cessation of urge to Smoke, satiating nicotine desire, nico for manufacturing an oral pharmaceutical composition com tine-replacement therapy, or Smoking cessation therapy prising the steps of: (a) preparing a gel fill composition comprising administering to a subject in need thereof any of comprising a first Solution, a flavor Solution, and a Sweetener the oral pharmaceutical compositions described herein. Solution wherein: (i) the first solution comprises one or more 0049. Another embodiment described herein is a phar hydrophilic vehicles, thickening agents, flavors, and excipi maceutical composition comprising a soft dosage form ents and is mixed at a temperature between 30-70° C. until comprising a shell encapsulating a liquid matrix, wherein dissolved; (ii) the flavor solution comprises one or more the shell comprises: (a) about 10% to about 40% gelatin, 150 hydrophilic vehicle and flavor and is mixed at a temperature Bloom; (b) about 1% to about 20% gelatin, 100 Bloom; (c) between 30-70° C. until dissolved; (iii) the sweetener solu about 1% to about 10% gelatin hydrolysate; (d) about 10% tion comprises one or more Sweetener in one or more solvent to about 40% glycerin; (e) about 10% to about 40% maltitol; and nicotine and mixing until dissolved; and (iv) combining (f) about 0.05% to about 2% citric acid; (g) about 1% to the first solution, flavor solution and sweetener solution and about 5% xylitol: (h) about 0.05% to about 2% sucralose: (i) mixing to homogenize; (b) preparing a gel mass composition about 0.05% to about 2% peppermint oil; and () about 10% comprising one or more film forming polymers, one or more to about 40% water; and the matrix comprises: (k) about plasticizers, one or more Sweeteners, one or more excipients 0.05% to about 5% polyethylene glycol 400: (1) about 10% and one or more solvents; (c) casting the gel composition to about 40% glycerin; (m) about 0.1% to about 5% xylitol; into films or ribbons using heat-controlled drums or Sur (n) about 10% to about 60% maltitol; (o) about 0.1% to faces; and (d) forming a soft dosage form comprising a about 10% glycine; (p) about 0.1% to about 5% sucralose; liquid matrix fill using rotary die encapsulation technology. (q) about 0.025% to about 2% menthol; (r) about 0.025% to 0.058 Another embodiment described herein is a soft about 2% peppermint oil: (s) about 1% to about 30% water; dosage form comprising an active pharmaceutical ingredient and (t) about 0.01% to about 5% nicotine polacrilex. in a liquid matrix produced by any of the methods described 0050. Another embodiment described herein is a method herein. In one aspect described herein, the dosage form is of delivering an active pharmaceutical ingredient to a patient stable for at least 1 year at 25° C. population unable to receive a conventional dosage form 0059 Another embodiment described herein is an oral comprising administering to the patient the oral pharmaceu pharmaceutical composition Suitable for chewing, sucking, tical composition comprising any of the soft dosage forms or buccal dissolution comprising a shell encapsulating a described herein. matrix, the shell comprising: (a) one or more film-forming 0051. Another embodiment described herein is a compo polymers; (b) one or more plasticizers; (c) one or more sition for delivering an active pharmaceutical ingredient to polymer modifiers; (d) one or more first Sweeteners; (e) one a patient population unable to receive a conventional dosage or more first solvents; and (f) optionally, one or more form comprising administering to the patient in need thereof excipients; and the matrix comprising: (g) one or more an oral pharmaceutical composition comprising any of the hydrophilic vehicles: (h) one or more flavors: (i) one or more Soft dosage forms described herein. second Sweeteners; () one or more second solvents; (k) 0052 Another embodiment described herein is a phar bismuth Subsalicylate; and (1) optionally, one or more excipi maceutical combination comprising any of the compositions ents. In one aspect described herein, the film-forming poly described herein and one or more additional therapeutic mer comprises one or more of gelatin, partially hydrolyzed compounds. In one aspect described herein, the one or more gelatin, hydrolyzed gelatin, hydrolyzed collagen, or combi additional therapeutic compound comprises bupropion or nations thereof. In another aspect described herein, the Varenicline. plasticizer comprises one or more of glycerol, maltitol, 0053 Another embodiment described herein is a method mannitol. Xylitol, lycasin, or combinations thereof. In for treating for treating, retarding the progression of pro another aspect described herein, the polymer modifier com phylaxis of delaying the onset of ameliorating, reducing the prises one or more of citric acid, acetic acid, lactic acid, symptoms of or promoting health, including but not limited malic acid, tartaric acid, or combinations thereof. In another to cessation of urge to Smoke, satiating nicotine desire, aspect described herein, the hydrophilic vehicle comprises nicotine-replacement therapy, or Smoking cessation therapy propylene glycol, polyethylene glycol 400, polyvinylpyr comprising administering to a subject in need thereof any of rolidone K30, glycerin, sorbitol, xylitol, maltitol, or combi the pharmaceutical combinations described herein. nations thereof. In another aspect described herein, the first 0054 Another embodiment described herein is a phar Sweetener comprises sucralose, aspartame, Stevia, acesul maceutical dosage form for satiating nicotine desire, nico fame potassium, Xylitol, or combinations thereof. In another tine-replacement therapy, or Smoking cessation therapy aspect described herein, the flavoring comprises citric acid, comprising any of the pharmaceutical compositions lactic acid, sodium citrate, orange flavor, eucalyptol, pep described herein. permint oil, methyl salicylate, glycine, or combinations 0.055 Another embodiment described herein is a method thereof. In another aspect described herein, the second for satiating nicotine desire, nicotine-replacement therapy, Sweetener comprises mannitol, maltitol. Xylitol, thaumatin, or Smoking cessation therapy comprising administering one glycyrrhizic acid salts, acesulfame potassium, acesulfame US 2016/0279056A1 Sep. 29, 2016

salts, sucralose, aspartame, Stevia, or combinations thereof. Bloom; (b) about 1% to about 20% gelatin, 100 Bloom; (c) In another aspect described herein, the excipients comprise about 1% to about 10% gelatin hydrolysate; (d) about 10% one or more flavorings, colorings, hygroscopic polymers, to about 40% glycerin; (e) about 10% to about 40% maltitol; opacifiers, thickening agents, Surfactants, or pharmaceuti (f) about 0.05% to about 2% citric acid; (g) about 1% to cally acceptable excipients. In another aspect described about 5% xylitol: (h) about 0.05% to about 2% sucralose; herein, the matrix is a liquid, flowable gel, or viscous and (i) about 10% to about 40% water; and the matrix semi-solid. In another aspect described herein, the shell comprises: (i) about 0.05% to about 5% polyethylene glycol comprises: (a) about 10% to about 50% of one or more 400; (k) about 0.5% to about 5% glycerin: (1) about 1% to film-forming polymers; (b) about 10% to about 60% of one about 15% propylene glycol; (m) about 10% to about 40% or more plasticizers; (c) about 0.01% to about 5% of one or sorbitol; (n) about 0.1% to about 5% xylitol; (o) about 0.05% more polymer modifiers; (d) about 0.1% to about 5% of one to about 5% sucralose: (p) about 0.025% to about 2% or more first sweeteners; (e) about 5% to about 50% of one menthol; (q) about 0.025% to about 2% peppermint oil; (r) or more first solvents; and (f) optionally, one or more about 1% to about 20% water; and (s) about 20% to about excipients; and the matrix comprises: (g) about 20% to about 80% bismuth subsalicylate. 70% of one or more hydrophilic vehicles: (h) about 0.05% 0062 Another embodiment described herein is a method to about 1% of one or more flavors: (i) about 0.25% to about of delivering an active pharmaceutical ingredient to a patient 5% of one or more second sweeteners; () about 1% to about population unable to receive a conventional dosage form 20% of one or more second solvents; (k) about 20% to about comprising administering to the patient the oral pharmaceu 80% of bismuth subsalicylate; and (1) optionally, one or tical composition comprising any of the soft dosage forms more excipients. In another aspect described herein, the shell described herein. comprises: (a) about 10% to about 40% gelatin, 150 Bloom: 0063 Another embodiment described herein is a compo (b) about 1% to about 20% gelatin, 100 Bloom; (c) about 1% sition for delivering an active pharmaceutical ingredient to to about 10% gelatin hydrolysate; (d) about 10% to about a patient population unable to receive a conventional dosage 40% glycerin; (e) about 10% to about 40% maltitol: (f) about form comprising administering to the patient in need thereof 0.05% to about 2% citric acid; (g) about 1% to about 5% an oral pharmaceutical composition comprising any of the xylitol: (h) about 0.05% to about 2% sucralose; and (i) about Soft dosage forms described herein. 10% to about 40% water. In another aspect described herein, 0064. Another embodiment described herein is a phar the matrix comprises: (a) about 0.05% to about 5% poly maceutical combination comprising any of the compositions ethylene glycol 400; (b) about 0.5% to about 5% glycerin; described herein and one or more additional therapeutic (c) about 1% to about 15% propylene glycol; (d) about 10% compounds. In one aspect described herein, the one or more to about 40% sorbitol; (e) about 0.1% to about 5% xylitol; additional therapeutic compound comprises one or more of (f) about 0.05% to about 5% sucralose; (g) about 0.025% to cimetidine, ranitidine, famotidine, ondansetron, omeprazole, about 2% menthol: (h) about 0.025% to about 2% pepper lansoprazole, rabeprazole, esomeprazole, pantoprazole, cal mint oil: (i) about 1% to about 20% water; and () about 20% cium Supplements, calcium hydroxide, alluminum hydrox to about 80% bismuth subsalicylate. In another aspect ide, magnesium hydroxide, or combinations thereof. described herein, the shell comprises: (a) about 19% gelatin, 0065. Another embodiment described herein is a method 150 Bloom; (b) about 13% gelatin, 100 Bloom; (c) about 2% for treating for treating, retarding the progression of pro gelatin hydrolysate; (d) about 22% glycerin; (e) about 14% phylaxis of delaying the onset of ameliorating, reducing the maltitol: (f) about 0.5% citric acid; (g) about 2.5% xylitol; symptoms of or promoting health, including but not limited (h) about 0.2% sucralose; and (i) about 29% water; and the to of one or more of one or more of inflammation of the matrix comprises: (i) about 1% polyethylene glycol 400; (k) gastrointestinal tract, neoplasia, hyperthyroidism, hypercal about 2% glycerin; (1) about 6% propylene glycol; (m) about cemia, hyperparathyroidism, parathyroid carcinoma, indi 27% sorbitol; (n) about 3% xylitol; (o) about 0.2% sucral gestion, heartburn, nausea, flatulence, bloating, acid reflux, ose: (p) about 0.04% menthol; (q) about 0.04% peppermint irritable bowels, constipation, diarrhea comprising adminis oil (r) about 11% water; and (s) about 47% bismuth tering to a subject in need thereof the pharmaceutical subsalicylate. In another aspect described herein, the ratio of combination comprising administering to a subject in need the active pharmaceutical ingredient to a combined weight thereof any of the oral pharmaceutical combinations percentage of the hydrophilic vehicle, flavor, sweetener, described herein. solvent and excipient is about 1:0.01 to about 1:20. 0066. Another embodiment described herein is a phar 0060 Another embodiment described herein is a method maceutical dosage form for treating or alleviating indiges for treating, retarding the progression of prophylaxis of tion, heartburn, nausea, flatulence, bloating, acid reflux, delaying the onset of ameliorating, or reducing the Symp diarrhea, or other discomforts of the stomach and gastroin toms of, or promoting health, including but not limited to of testinal tract, comprising any of the pharmaceutical compo one or more of inflammation of the gastrointestinal tract, sitions described herein. neoplasia, hyperthyroidism, hypercalcemia, hyperparathy 0067. Another embodiment described herein is a method roidism, parathyroid carcinoma, indigestion, heartburn, nau for treating or alleviating indigestion, heartburn, nausea, sea, flatulence, bloating, acid reflux, irritable bowels, con flatulence, bloating, acid reflux, diarrhea, or other discom stipation, diarrhea, comprising administering to a Subject in forts of the stomach and gastrointestinal tract, comprising need thereof any of the oral pharmaceutical compositions administering one or more dosage forms comprising any of described herein. the pharmaceutical compositions described herein. 0061 Another embodiment described herein is a phar 0068 Another embodiment described herein is a means maceutical composition comprising a soft dosage form for treating or alleviating indigestion, heartburn, nausea, comprising a shell encapsulating a liquid matrix, wherein flatulence, bloating, acid reflux, diarrhea, or other discom the shell comprises: (a) about 10% to about 40% gelatin, 150 forts of the stomach and gastrointestinal tract, comprising US 2016/0279056A1 Sep. 29, 2016 administering one or more dosage forms comprising any of agent, active ingredient, compound, or Substance, composi the pharmaceutical compositions described herein. tions, or mixtures thereof, that provide a pharmacological, 0069. Another embodiment described herein is a method often beneficial, effect. for manufacturing an oral pharmaceutical composition com (0078. The terms “dosage” or “dose” as used herein prising the steps of: (a) preparing a gel fill composition denotes any forms of the active ingredient formulation that comprising a color solution, a flavor Solution and a gel contain an amount Sufficient to produce a therapeutic effect Solution wherein: (i) the color Solution comprises one or with a single administration. The dosage form described more colors and excipient in one or more solvents and mixed herein is for oral administration. The preferred oral dosage at a temperature between 30-50° C. until dissolved; (ii) the forms described herein are soft gelatin capsules or “soft flavor Solution comprises one or more of plasticizer, menthol gels.” and flavor and mixed at a temperature between 30-50° C. 007.9 The terms “active pharmaceutical ingredient load” until dissolved; (iii) the gel Solution comprises soaking one or "drug load’ as used herein refers to the quantity (mass) of or more film forming polymer, plasticizer, Sweeteners in one the active pharmaceutical ingredient comprised in a single or more solvents, then heated at a temperature between soft capsule fill. 30-70° C. until dissolved; (iv) combining the color solution, 0080. The term “formulation' or “composition” as used flavor Solution, and gel Solution and adding bismuth Sub herein refers to the drug in combination with pharmaceuti salicylate and mixing at a temperature of 20-60° C. until cally acceptable excipients. This term includes orally admin dissolved; (b) preparing a gel mass composition comprising istrable formulations as well as formulations administrable one or more film forming polymers, one or more plasticiz by other means. ers, one or more Sweeteners, one or more excipients and one 0081. The term “titration' as used herein refers to the or more solvents; (c) casting the gel composition into films incremental increase in drug dosage to a level that provides or ribbons using heat-controlled drums or Surfaces; and (d) forming a soft dosage form comprising a liquid matrix fill the optimal therapeutic effect. using rotary die encapsulation technology. I0082. The term “treating” refers to administering a 0070 Another embodiment described herein is a soft therapy in an amount, manner, or mode effective to improve dosage form comprising an active pharmaceutical ingredient a condition, symptom, or parameter associated with a dis in a liquid matrix produced by any of the methods described order. herein. In one aspect described herein, the dosage form is I0083. The term “conventional dosage from means a stable for at least 1 year at 25° C. tablet or pill. I0084. The term “prophylaxis' refers to preventing or BRIEF DESCRIPTION OF THE DRAWINGS reducing the progression of a disorder, either to a statistically significant degree or to a degree detectable to one skilled in 0071. Further advantageous features of the present dis the art. closure will become more apparent with the following detailed description when taken with reference to the accom I0085. The term “substantially as used herein means to a panying drawings, each according to an aspect of the present great or significant extent, but not completely. disclosure: I0086. As used herein, all percentages (%) refer to weight 0072 FIG.1. Dissolution of a nicotine Liquisoft capsule. percent unless noted otherwise. I0087. The term “about” as used herein refers to any DETAILED DESCRIPTION values, including both integers and fractional components that are within a variation of up to +10% of the value 0073. Described herein are oral pharmaceutical compo modified by the term “about.” sitions of comprising chewable. Suckable, or dissolvable soft 0088. As used herein, “a” or “an” means one or more gel capsules with various flowable fill compositions. unless otherwise specified. Terms such as “include.” 0074 The oral pharmaceutical compositions described “including.” “contain,” “containing” and the like mean herein are soft gel capsules, e.g., “LiquiSoftTM capsules, “comprising.” Suitable for chewing, Sucking, or buccal dissolution and having pleasing organoleptic properties comprising flowable I0089. The term 'or' can be conjunctive or disjunctive. 0090. One embodiment described herein, is an oral phar or liquid matrix fills of a variety of active pharmaceutical maceutical composition comprising a chewable. Suckable, ingredients, or combinations thereof, and methods for prepa or dissolvable soft capsule shell encapsulating a liquid ration thereof. matrix fill comprising one or more active pharmaceutical 0075. The term “pharmaceutical combination” as used herein refers to either a pharmaceutical composition com ingredients. In one embodiment described herein, the phar prising one or more active pharmaceutical ingredient and maceutical composition comprises that shown in Table 1. one or more second therapeutic compounds or a pharma ceutical composition comprising an active pharmaceutical TABLE 1. ingredient coadministered with a second therapeutic com Exemplary Liquisoft Composition pound. 0076. The phrase “organoleptic properties' as used Exemplary Ingredients % weight herein refers to the sensory aspects experienced by one or Capsule Shell Formulation more subjects, including but not limited to, sight, Smell, Polymer(s) 20-60 taste, mouth feel, moisture content/dryness, plasticity, chew Plasticizer(s) 30-70 ability, dissolution, residue, and aftertaste. Polymer Modifier(s) O-2 0077. The terms “active ingredient’ or “active pharma Sweetener(s) O-SO ceutical ingredient’ as used herein refer to a pharmaceutical US 2016/0279056A1 Sep. 29, 2016 11

TABLE 1-continued TABLE 2 Exemplary Liquisoft Composition Exemplary Liquisoft Composition Exemplary Ingredients % weight Weight Percentage Solvent(s) 1O-40 Component Exemplary Component (%) Excipients: flavorings, O.1-10 colorings, opacifiers, etc. Capsule Shell Formulation TOTAL 100% Polymers Gelatin, 150 Bloom 1O-40 Matrix Fill Formulation Gelatin, 100 Bloom 1-2O Gelatin Hydrolysate O-7 Hydrophilic Vehicle(s) 20-90 Hydrolyzed Collagen O-7 Flavoring(s) O-10 Plasticizer(s) Glycerol 1O-SO Sweetener(s) O-SO Maltitol (Lycasin (R) 1-3O Optional Excipient(s) O-2S Xylitol O-2O Solvent(s) O-2S Sweeteners Sucralose O-5 Active Pharmaceutical O-60 Polymer Citrate O-2 Ingredient(s) (APIs) Modifier Solvent Water 1O-40 TOTAL 100% TOTAL 100% Matrix Fill Formulation 0091. One embodiment described herein is an oral phar Hydrophilic Propylene Glycol O-2O maceutical composition Suitable for chewing, sucking, or Vehicle Polyethylene Glycol 400 1O-SO Polyvinylpyrrollidone K30 O-2 buccal dissolution. In one embodiment, the composition Flavors Citric Acid O-3 comprises a gel mass Suitable for forming soft gel capsules. Lactic Acid O-3 In another embodiment, the composition comprises a liquid Sodium Citrate O-3 matrix fill. In one embodiment, the composition comprises Sweeteners Maltitol (Lycasin (R) 20-70 Mannitol O-5 a flowable gel matrix fill. In another embodiment, the Sucralose O-2 composition comprises a viscous semi-solid matrix fill. In Thaumatin (Talin (R) O-5 another embodiment, the composition comprises a soft gel Glycyrrhizic acid salts O-5 (MagnaSweet (R) capsule and a liquid matrix fill. In one embodiment, the Excipients O-2S pharmaceutical composition provides a “burst' of Sweet Solvent Water O-15 ened flavored liquid comprising one or more active phar Active e.g., Dextromethorphan O-15 maceutical ingredients to the oral cavity when a subject Pharmaceutical Hydrobromide manipulates the dosage form within the mouth. The Subject Ingredients may bite or chew the dosage form, Suck the dosage form, or (API) allow the dosage form to slowly dissolve in the oral cavity. TOTAL 100% Upon rupturing the gel capsule shell by chewing, sucking, or dissolution within the mouth, the liquid matrix is released and provides a burst of liquid sensation to the Subjects oral 0095. In one embodiment described herein, the soft cap cavity. The sensation may be Sweet, flavored, cooling, or a Sule shell comprises one or more film-forming polymers. In combination thereof. One or more of these “sensations' can one embodiment, the polymer comprises gelatin having a be used to mask poor tasting active pharmaceutical ingre Bloom strength of about 50 to about 400 Bloom, hydrolyzed dients or provide Soothing sensations to a subjects oral gelatin, gelatin hydrolysate, hydrolyzed collagen, Sodium mucosa, sinuses, or throat, for example. and calcium alginate; natural and modified starch and starch 0092. One embodiment described herein is a soft capsule hydrolysates, pectins and amylopectins, cellulose deriva shell comprising one or more film-forming polymers, one or tives, such as or hydroxypropylmethylcellulose (HPMC), more plasticizers, one or more polymer modifiers, one or methylcellulose, cellulose, or combinations thereof. In one more solvents, one or more Sweeteners, and optionally, one aspect described herein the polymer comprises one or more or more pharmaceutically acceptable excipients, including gelatins or gelatin hydrolysates. but not limited to coloring agents, flavorings, opacifiers, 0096. Examples of gelatin compositions that are useful hygroscopic polymers, thickening agents, Surfactants or the for the pharmaceutical compositions described herein com like. prise acid bone gelatin, pig skin gelatin, chicken skin gelatin, fish gelatin, acid hide gelatin, gelatin hydrolysate, lime bone 0093 Chewable soft capsule shells are described in U.S. gelatin, or combinations thereof. Gelatins can be classified Pat. Nos. 6,258,380; 8,097,279; 8,241,665; 8,414,916; and as either Type A or Type B gelatin. Type Agelatin is derived 8.765,174, each of which is in incorporated by reference from the acid hydrolysis of collagen (e.g., acid bone gelatin herein for Such teachings. or pig skin gelatin), while Type B gelatin (e.g., lime bone 0094. Another embodiment described herein is a matrix gelatin) is derived from the alkaline hydrolysis of collagen. fill comprising one or more hydrophilic vehicles, one or Traditionally, bovine bones and skins are used as raw more Sweeteners, one or more flavorings, one or more materials for manufacturing Type A and Type B gelatin, Solvents, optionally, one or more excipients, and one or more while porcine skins are used extensively for manufacturing active pharmaceutical ingredients. In one embodiment Type A gelatin. In addition, at neutral pH values, Type A described herein, the composition comprises that shown in gelatins (acid processed gelatins) are typically net cationic Table 2. (e.g., isoelectric point of about 7-9) and Type B gelatins US 2016/0279056A1 Sep. 29, 2016

(alkali processed gelatins) are typically net anionic (e.g., 0103) In one embodiment, the one or more polymer isoelectric point of about 4.5-5.3). Type Agelatin typically comprises a weight percentage of about 20% to about 60% has higher plasticity and elasticity than type B gelatin; type by weight of the shell, including each integer within the B gelatin typically has higher gel strength than type A specified range. In another embodiment, the one or more gelatin. polymers comprise about 20% to about 50%, about 25% to 0097. The strength of gelatin compositions is typically about 55%, or about 30% to about 45% by weight of the defined by their Bloom strength or grade. The Bloom test shell. In one aspect, the total polymer comprises about 20%, determines the weight (in grams) needed by a 0.5-inch about 25%, about 30%, about 35%, about 40%, about 45%, diameter probe to deflect the surface of a gel 4 mm without about 50%, about 55%, or about 60% by weight of the shell. breaking it. The result is expressed as “Bloom’ or “Bloom In another aspect, the total one or more polymers comprise strength.” The pharmaceutical compositions described about 32% by weight of the shell. In another aspect, the total herein utilize gelatins with Bloom strengths in the range of one or more polymers comprise about 30%, about 31%, about 50 Bloom to about 400 Bloom, including each integer about 33%, 34% or about 37% by weight of the shell. within the specified range. In one embodiment, Bloom 0104. In another embodiment, the one or more polymers strengths for pharmaceutical compositions described herein comprise gelatin having a Bloom of about 150 and a weight are about 50 Bloom to about 250 Bloom including each percentage of about 10% to about 40% by weight of the integer within the specified range. In some embodiments, the shell, including each integer within the specified range. In gelatin Bloom strength is about 50 Bloom, about 80 Bloom, one embodiment, gelatin having a Bloom of about 150 about 100 Bloom, about 120 Bloom, about 150 Bloom, comprises about 10% to about 30%, about 15% to about about 180 Bloom, about 200 Bloom, or about 250 Bloom. In 30%, about 15% to about 25%, or about 15% to about 20% one embodiment, the gelatin Bloom strength is 100 Bloom. by weight of the shell. In one aspect, gelatin having a Bloom In another embodiment, the gelatin Bloom strength is 150 of about 150 comprises about 10%, about 15%, about 20%, Bloom. In another embodiment, the gelatin Bloom strength about 25%, about 30%, about 35%, or about 40% by weight is 195 Bloom. In another embodiment, the gelatin Bloom of the shell. In another aspect, gelatin having a Bloom of strength is 200 Bloom. In another aspect, the one or more about 150 comprises about 19% by weight of the shell. In film-forming polymers comprise one or more of gelatin, another aspect, gelatin having a Bloom of about 150 com partially hydrolyzed gelatin, hydrolyzed gelatin, or combi prises about 14%, about 16%, about 18%, about 20%, or nations thereof. about 22% by weight of the shell. 0098. In one embodiment described herein, the one or 0105. In another embodiment, the one or more polymers more polymers comprise one or more gelatins having a comprise a gelatin having a Bloom of about 100 and a Bloom of about 100. In another aspect, the one or more weight percentage of about 1% to about 30% by weight of polymers comprise one or more gelatins having a Bloom of the shell, including each integer within the specified range. about 150. In another aspect, the one or more polymers In another embodiment, gelatin having a Bloom of about comprise one or more of partially hydrolyzed gelatin, hydro 100 comprises about 1% to about 20%, 1% to about 15%, lyzed gelatin, hydrolyzed collagen, or combinations thereof. about 1% to about 10%, or about 5% to about 10% by weight 0099. In another embodiment described herein, the soft of the shell. In one aspect, gelatin having a Bloom of about capsule shell comprises one or more plasticizers. As used 100 comprises about 1%, about 5%, about 10%, about 15%, herein, a plasticizer is a Substance, often a polyol, that about 20%, about 25% or about 30% by weight of the shell. provides flexibility and softens the capsule. In one embodi In another aspect, gelatin having a Bloom of about 100 ment, the plasticizer comprises one or more of glycerol, comprises 8% by weight of the shell. In another aspect, sorbitol, mannitol, maltitol (Lycasin(R), xylitol (Xylisorb(R), gelatin having a Bloom of about 100 comprises about 5%, or combinations thereof. In one aspect, the plasticizer com about 7%, about 10%, 15%, 18% or about 28% by weight of prises glycerol, Sorbitol, or combinations thereof. In one the shell. aspect, the plasticizer comprises glycerol, maltitol (Lyca 0106. In another embodiment, the one or more polymers sin(R), xylitol, or combinations thereof. comprise gelatin hydrolysate having a weight percentage of 0100. In another embodiment described herein, the soft about 0 to about 7% by weight of the shell, including each capsule shell comprises one or more Sweeteners. In one integer within the specified range. In one embodiment, embodiment, the Sweetener comprises one or more of Sucral gelatin hydrolysate comprises about 0.25% to about 6.75%, ose, Xylitol, aspartame, acesulfame potassium, acesulfame about 0.50% to about 6.50%, about 1% to about 6%, or salts, Steviol glycosides (e.g., Stevia(R, Truvia(R), thaumatin about 1.5% to about 5.5% by weight of the shell. In one (e.g., Talin R.), glycyrrhizic acid salts (MagnaSweet(R), or aspect, gelatin hydrolysate comprises about 0%, about 2%, combinations thereof. In one aspect, the Sweetener com about 4%, or about 7% by weight of the shell. In another prises Sucralose. aspect, the gelatin hydrolysate comprises about 5% by 0101. In another embodiment described herein, the soft weight of the shell. In another aspect, the gelatin hydrolysate capsule shell comprises one or more polymer modifiers. In comprises about 2%, about 4%, about 4.5%, about 5.5%, or one embodiment, the polymer modifier comprises an about 6% by weight of the shell. organic acid. In another embodiment, the polymer modifiers 0107. In another embodiment, the one or more polymers comprise one or more of citric acid, acetic acid, lactic acid, comprise hydrolyzed collagen at a weight percentage of malic acid, tartaric acid, glutamic acid, aspartic acid, malic about 0% to about 7% by weight of the shell, including each acid, Succinic acid, fumaric acid, or combinations thereof. In integer within the specified range. In one embodiment, one aspect, the polymer modifier comprises citric acid. hydrolyzed collagen comprises about 0.25% to about 6.75%, 0102. In another embodiment, the soft capsule shell com about 0.50% to about 6.50%, about 1% to about 6%, or prises one or more solvents. In one aspect, the solvent about 1.5% to about 5.5% by weight of the shell. In one comprises water. aspect, hydrolyzed collagen comprises about 0%, about 2%, US 2016/0279056A1 Sep. 29, 2016

about 4%, or about 7% by weight of the shell. In another of the shell. In another aspect, the polymer modifier com aspect, hydrolyzed collagen comprises about 5% by weight prises about 0.5% by weight of the shell. In another aspect, of the shell. In another aspect, hydrolyzed collagen com the polymer modifier comprises about 0.25%, about 0.3%, prises about 4%, about 4.5%, about 5%, about 5.5%, or or about 0.6% by weight of the shell. about 6% by weight of the shell. 0113. In another embodiment, the polymer modifier com 0108. In another embodiment, one or more plasticizers prises citrate having a weight percentage of about 0.01% to comprise a weight percentage of about 30% to about 70% by about 2% by weight of the shell, including each integer weight of the shell, including each integer within the speci within the specified range. In another embodiment, citrate fied range. In one embodiment, the one or more plasticizers comprises about 0.25% to about 1.5%, about 0.25% to about comprise about 30% to about 60%, about 30% to about 50%, 1%, or about 0.25% or about 0.75% by weight of the shell. or about 35% to about 45% by weight of the shell. In one In one aspect, citrate comprises about 0%, about 0.25%, aspect, one or more plasticizers comprise about 30%, about about 0.50%, about 0.75%, about 1%, about 1.25%, about 35%, about 40%, about 45%, about 50%, about 55%, about 1.50%, about 1.75%, or about 2.0% by weight of the shell. 60%, about 65%, or about 70% by weight of the shell. In In another aspect, citrate comprises about 0.5% by weight of another aspect, the total plasticizer comprises about 43% by the shell. In another aspect, citrate comprises about 0.25%, weight of the shell. In another aspect, the total plasticizer about 0.3%, or about 0.6% by weight of the shell. comprises about 36%, about 39%, about 40%, about 41%, 0114. In another embodiment, the one or more sweeten about 42%, about 44%, or about 45% by weight of the shell. ers comprise Sucralose having a weight percentage of about 0109. In another embodiment, the one or more plasticiz 0.01% to about 5% by weight of the shell, including each ers comprise glycerol. Xylitol, maltitol, or a combination integer within the specified range. In one embodiment, thereof and comprise a weight percentage of about 10% to sucralose comprises about 0.1% to about 0.9%, about 0.1% about 50% by weight of the shell, including each integer to about 0.75%, or about 0.1% to about 0.5% by weight of within the specified range. In another embodiment, glycerol the shell. In one aspect, Sucralose comprises about 0%; comprises about 10% to about 40%, about 15% to about about 0.25%, about 0.50%, about 0.75%, or about 1% by 35%, about 15% to about 30%, or about 20% to about 25% weight of the shell. In another aspect, Sucralose comprises by weight of the shell. In one aspect, glycerol comprises about 0.2%. In another aspect, Sucralose comprises about about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% by weight 0.1%, about 0.15%, about 0.25%, or about 0.3% by weight of the shell. In another aspect, glycerol comprises about 24% of the shell. by weight of the shell. In another aspect, glycerol comprises 0.115. In another embodiment, the one or more sweeten about 19%, about 20%, about 21%, about 22%, about 23%, ers comprise xylitol having a weight percentage of about about 24%, or about 25% by weight of the shell. 0.01% to about 5% by weight of the shell, including each 0110. In another embodiment, the one or more plasticiz integer within the specified range. In one embodiment, ers comprise Xylitol having a weight percentage of 0% to xylitol comprises about 0.1% to about 4%, about 0.1% to about 20% by weight of the shell, including each integer about 3%, or about 0.5% to about 2.5% by weight of the within the specified range. In one embodiment, Xylitol shell. In one aspect, xylitol comprises about 0%; about comprises about 1% to about 15%, about 1% to about 10%, 0.25%, about 0.50%, about 0.75%, about 1%, about 1.5%, or about 1% to about 5% by weight of the shell. In one about 2%, or about 2.5% by weight of the shell. In another aspect, xylitol comprises about 0%, about 5%, about 10%, aspect, Xylitol comprises about 2.5%. In another aspect, about 15%, or about 20% by weight of the shell. In another xylitol comprises about 1.5%, about 2%, about 2.25%, or aspect, xylitol comprises about 3% by weight of the shell. In about 2.75% by weight of the shell. another aspect, xylitol comprises about 0.5%, about 1%, 0116. In another embodiment, one or more solvents com about 4%, or about 5% by weight of the shell. prise about 10% to about 40% by weight of the shell, 0111. In another embodiment, the one or more plasticiz including each integer within the specified range. In another ers comprise maltitol having a weight percentage of about embodiment, the solvents comprise about 10% to about 1% to about 30% by weight of the shell, including each 35%, about 15% to about 30%, or about 20% to about 30% integer within the specified range. In one embodiment, by weight of the shell. In another aspect, the solvents maltitol comprises about 1% to about 30%, about 5% to comprise about 10%, about 15%, about 20%, about 25%, about 25%, about 10% to about 25%, or about 15% to about about 30%, about 35%, or about 40% by weight of the shell. 20% by weight of the shell. In one aspect, maltitol comprises In another aspect, the solvents comprise 23% by weight of about 1%, about 5%, about 10%, about 15%, about 20%, the shell. In another aspect, the Solvents comprise about about 25%, or about 30% by weight of the shell. In another 17%, about 20%, about 25%, or about 30% by weight of the aspect, maltitol comprises about 17% by weight of the shell. shell. In another aspect, maltitol comprises about 15%, about 16%, 0117. In another embodiment, the solvent comprises or about 18% by weight of the shell. water having a weight percentage of about 10% to about 0112. In another embodiment, the one or more polymer 40% by weight of the shell, including each integer within the modifiers comprise about 0.01% to about 2% by weight of specified range. In another embodiment, water comprises the shell, including each integer within the specified range. about 10% to about 35%, about 15% to about 30%, or about In one embodiment, the one or more polymer modifiers 20% or about 30% by weight of the shell. In another aspect, comprise about 0.25% to about 1.5%, about 0.25% to about water comprises about 10%; about 15%, about 20%, about 1%, or about 0.25% to about 0.75% by weight of the shell. 25%, about 30%, about 35%, or about 40% by weight of the In one aspect, the polymer modifier comprises about 0%. shell. In another aspect, water comprises 23% by weight of about 0.25%, about 0.50%, about 0.75%, about 1%, about the shell. In another aspect, water comprises about 17%, 1.25%, about 1.50%, about 1.75%, or about 2.0% by weight about 20%, about 25%, or about 30% by weight of the shell. US 2016/0279056A1 Sep. 29, 2016

0118. In another embodiment, the ratio of total polymer capsule size within the specified range (e.g., 2 round, 3 to total plasticizer in the shell comprises about 1:1 to about round, 4 round, 5 round, 6 round, 7 round, 8 round, 10 round, 1:2, including each ratio within the specified range. In 12 round, 16 round, 20 round or 28 round). In another another embodiment, the ratio of total polymer to total embodiment described herein, the soft capsule shell and plasticizer in the shell is about 1:1 to about 1:1.8, about 1:1 encapsulated matrix fill comprises an outer dimension from to about 1:1.6, about 1:1 to about 1:4. In one aspect, the ratio about 2 oblong to about 22 oblong including all iterations of of total polymer to total plasticizer in the shell is about 1:1.1, capsule size within the specified range (e.g., 2 oblong, 3 about 1:1.2, about 1:1.3, about 1:1.4, about 1:1.5, about oblong, 4 oblong, 5 oblong, 6 oblong, 7 oblong, 8 oblong, 10 1:1.6, about 1:1.7, about 1:1.8, about 1:1.9, or about 1:2. In oblong, 11, oblong, 12 oblong, 14 oblong, 16 oblong, 20 another aspect, the ratio of total polymer to total plasticizer oblong, or 22 oblong). Dimension specifications of Soft in the shell is about 1:1.3. In another aspect, the ratio of total capsules and tablets are known to those skilled in the art. See polymer to total modifier in the shell is about 1:0.75, about Remington's Essentials of Pharmaceutics, Pharmaceutical 1:1.25, about 1:1.5, or about 1:1.75. Press Publishing Company, London, UK, 1 Edition, 2013, 0119. In another embodiment, the ratio of total polymer which is incorporated by reference herein for Such teachings. to total polymer modifier in the shell comprises about 1:0.01 I0123. In one embodiment, the hydrophilic vehicle may be to about 1:0.1, including each ratio within the specified anhydrous and compatible with soft gelatin capsules. Non range. In one embodiment, the ratio of total polymer to total limiting exemplary vehicles comprise CapmulR MCM, polymer modifier in the shell is about 1:0.01 to about 1:0.08, Captex R 355, Cremophor R. RH 40, Croscarmellose, about 1:0.01 to about 1:0.06, or about 1:0.01 to about 1.04. Crospovidone, Crospovidone CL, Crospovidone CL-F, In one aspect, the ratio of total polymer to total plasticizer Crospovidone CL-M, Imwitor R 742, Kollidon R. CL, Kol in the shell is about 1:0.01, about 1:0.02, about 1:0.03, about lidon(R) CL-F, Kollidon(R) CL-M, LabrafacTM Lipophile WL 1:0.04, about 1:0.05, about 1:0.06, about 1:0.07, about 1349, Labrafil.R M2125CS, Labrasol(R), Lutrol(R) F 68, 1:0.08, about 1:0.09, or about 1:1. In another aspect, the ratio MaisineTM35-1, mannitol, Miglyol(R) 812, Pearlitol(R) Flash, of total polymer to total polymer modifier in the shell is Peceol R, PlurolR Oleigue CC 497, Povidone K 17, Povi about 1:0.02. In another aspect, the ratio of total polymer to done K 30, polyethylene glycol 200, polyethylene glycol total modifier in the shell is about 1:0.01, or about 1:0.03. 400, polyethylene glycol 600, polyethylene glycol 800, 0120 In one embodiment, Soft capsules are made using a polyethylene glycol 1000, polyethylene glycol 2000, poly rotary die apparatus as described in U.S. Pat. Nos. 5.459, ethylene glycol 3350, propylene glycol, glycerol, Lycasin 983; 5,146,730; and 6,482,516, each of which are incorpo 80/55, sorbitol special, xylitol, maltitol or mixtures thereof. rated by reference herein for Such teachings. In on embodiment the hydrophilic vehicle comprises one or 0121 Another embodiment described herein includes a more hydro-alcohols including polyethylene glycols of a process of manufacturing soft capsules comprising the phar molecular weight ranging from about 200 to about 8000, or maceutical compositions as described herein. The process a mixture or combination thereof. includes preparing a gel mass composition comprising one 0.124. In another embodiment, the hydrophilic vehicle or more polymers, one or more plasticizers, one or more may comprise a hygroscopic polymer. In one embodiment, polymer modifiers, one or more solvents, and appropriate the hygroscopic polymers include polyvinylpyrrolidone, flavorings, Sweeteners, coloring agents, or other excipients; copovidone, hydroxypropylmethylcellulose, hydroxypropy casting the gel mass into films or ribbons using heat lcellulose, ethyl cellulose, methylcellulose, and polyethyl controlled drums or Surfaces; and manufacturing a soft ene oxide. Suitable hygroscopic polymers include polyvinyl capsule comprising a matrix fill using rotary die technology. alcohol, a copolymer of polyvinylpyrrolidone and polyvinyl The thickness of the films or ribbons that form the soft acetate, hydroxypropyl cellulose, hydroxypropyl methylcel capsule shell is from about 0.010 inches (s0.254 mm) to lulose, hydroxyethyl cellulose, hydroxymethyl cellulose, about 0.050 inches (s.1.27 mm), including all integers within gelatin, polyethylene oxide, such as POLYOXTM 100,000 the specified range. The shell thickness can be about 0.010 600,000 MW, acacia, dextrin, cyclodextrins, starch, poly inch (s().254 mm), about 0.015 inch (s0.381 mm), about hydroxyethylmethacrylate, a water-soluble non-ionic 0.02 in (s0.508 mm), about 0.03 in (s0.762mm), about 0.04 polymethacrylate or copolymer thereof, a modified cellu in (s1.02 mm), or about 0.05 in (s1.27 mm). In one lose, a modified polysaccharide, a non-ionic gum, or a embodiment, the thickness is about 0.02 inches (s0.508 mm) non-ionic polysaccharide. to about 0.040 inches (s1.02 mm). In one embodiment, the 0.125. In another embodiment, the hydrophilic vehicle shell thickness is about 0.028 inches (s0.711 mm). In may comprise one or more lipids or lipophilic vehicles. In another embodiment, the shell thickness is about 0.033 one aspect, the lipid or lipophilic vehicle may be a liquid or inches (s0.838 mm). In another embodiment, the shell a solid or a semisolid lipid or lipophilic vehicle. Suitable thickness is about 0.038 inches (sO.965 mm). non-limiting liquid lipid or lipophilic vehicles comprise 0122. In one embodiment described herein, the soft cap olive oil, soybean oil, Sunflower oil, canola oil, palmitoleic sule shell described herein, encapsulates a matrix fill as acid, oleic acid, myristoleic acid, linoleic acid, arachidonic described herein. In another embodiment described herein, acid, paraffin oil, mineral oil, or a mixture or combination the soft capsule shell and encapsulated matrix fill comprises thereof. The lipid or lipophilic vehicle can be a semi-solid an outer dimension from about 2 oval to about 30 oval lipophilic vehicle Such as a polyethylene glycol glyceride including all iterations of capsule size within the specified ester, e.g., Gelucire R 33/01, GelucireR 37/02, Gelucire(R) range (e.g., 2 oval, 3 oval, 4 oval, 5 oval, 6 oval, 7 oval, 8 39/01, GelucireR 43/01, GelucireR 44/14, GelucireR 50702, oval, 10 oval, 12 oval, 16 oval, 20, or 30 oval). In another Gelucire(R) 50/13, GelucireR 53/10, or Gelucire R 62/02; a embodiment described herein, the soft capsule shell and paraffin wax, carnauba wax, or bee’s wax. encapsulated matrix fill comprises an outer dimension from I0126. In another embodiment, the hydrophilic vehicle about 2 round to about 28 round including all iterations of may comprise release regulators such as fatty acid salts, fatty US 2016/0279056A1 Sep. 29, 2016 acid esters, or fatty acid polyoxyethylene derivatives. The potassium hydroxide, Sodium bicarbonate, sodium borate, release regulator can also be a surfactant having a hydro Sodium carbonate, Sodium hydroxide, trolamine); Antifoam philic/lipophilic balance (HLB) value between about 2 and ing agents (dimethicone, simethicone); Antimicrobial pre about 40. The HLB characteristic of surfactants can be servatives (benzalkonium chloride, benzalkonium chloride determined in accordance with “Physical Pharmacy: Physi Solution, benzethonium chloride, benzoic acid, benzyl alco cal Chemical Principles in the Pharmaceutical Sciences, '' hol, butylparaben, cetylpyridinium chloride, chlorobutanol, Fourth Edition, pp. 371-373, A. Martin, Ed., Lippincott chlorocresol, cresol, dehydroacetic acid, ethylparaben, Williams & Wilkins, Philadelphia (1993), which is incor methylparaben, methylparaben Sodium, phenol, phenylethyl porated by reference herein for Such teachings. alcohol, phenylmercuric acetate, phenylmercuric nitrate, 0127. In another embodiment, the hydrophilic vehicle potassium benzoate, potassium Sorbate, propylparaben, pro may comprise emulsifying or solubilizing agents such as pylparaben Sodium, Sodium benzoate, sodium dehydroac acacia, cholesterol, diethanolamine, glyceryl monostearate, etate, sodium propionate, Sorbic acid, thimerosal, thymol); lanolin alcohols, lecithin, mono- and di-glycerides, Antioxidants (ascorbic acid, ascorbyl palmitate, butylated monoethanolamines, oleic acids, oleyl alcohols, poloxamer, hydroxyanisole, butylated hydroxytoluene, hypophospho polyoxyethylene 50 stearate, polyoxyl 35 castor oil, poly rous acid, monothioglycerol, propyl gallate, Sodium form oxyl 40 hydrogenated castor oil, polyoxyl 10 oleyl ether, aldehyde sulfoxylate, sodium metabisulfite, sodium thiosul polyoxyl 20 cetostearyl ether, polyoxyl 40 stearate, polysor fate, Sulfur dioxide, tocopherol, tocopherols excipient); bate 20, polysorbate 40, polysorbate 60, polysorbate 80, Buffering agents (acetic acid, ammonium carbonate, ammo propylene glycol diacetate, propylene glycol monostearate, nium phosphate, boric acid, citric acid, lactic acid, phos Sodium lauryl Sulfate, Sodium Stearate, Sorbitan monolau phoric acid, potassium citrate, potassium metaphosphate, rate, Sorbitan monooleate, Sorbitan monopalmitate, Sorbitan potassium phosphate monobasic, Sodium acetate, Sodium monostearate, Stearic acid, simethicone, trolamine, emulsi citrate, sodium lactate Solution, dibasic sodium phosphate, fying wax, or combinations thereof. monobasic sodium phosphate); Chelating agents (edetate 0128. In one embodiment described herein, the matrix fill disodium, ethylenediaminetetraacetic acid and salts, edetic comprises one or more hydrophilic vehicles. In another acid); Coating agents (sodium carboxymethylcellulose, cel aspect, the one or more hydrophilic vehicles comprise lulose acetate, cellulose acetate phthalate, ethylcellulose, propylene glycol, polyethylene glycol 400, polyvinylpyr gelatin, pharmaceutical glaze, hydroxypropyl cellulose, rolidone K30, or combinations thereof. hydroxypropyl methylcellulose, hydroxypropyl methylcel 0129. In another embodiment described herein, the lulose phthalate, methacrylic acid copolymer, methylcellu matrix fill comprises one or more flavorings. In one embodi lose, polyvinyl acetate phthalate, shellac, Sucrose, titanium ment, the one or more flavorings comprise citric acid, lactic dioxide, carnauba wax, microcrystalline wax, Zein); Colo acid, sodium citrate, anethole, benzaldehyde, ethyl Vanillin, rants (caramel, red, yellow, black or blends, ferric oxide); Eucalyptol, glycine, menthol, methyl salicylate, monoso Complexing agents (ethylenediaminetetraacetic acid and dium glutamate, orange flower oil, peppermint, peppermint salts (EDTA), edetic acid, gentisic acid ethanolamide, oxy oil, peppermint spirit, rose oil, stronger rose water, thymol. quinoline Sulfate); Desiccants (calcium chloride, calcium tolu balsam tincture, Vanilla, Vanilla tincture, Vanillin or Sulfate, silicon dioxide); Emulsifying and/or solubilizing combinations thereof. In one aspect, the flavorings comprise agents (acacia, cholesterol, diethanolamine (adjunct), glyc one or more of citric acid, acetic acid, lactic acid, malic acid, eryl monostearate, lanolin alcohols, mono- and di-glycer tartaric acid, or combinations thereof. In another aspect, the ides, monoethanolamine (adjunct), lecithin, oleic acid (ad flavorings comprise citric acid, lactic acid, or combinations junct), oleyl alcohol (stabilizer), poloxamer, thereof. polyoxyethylene 50 stearate, polyoxyl 35 castor oil, poly 0130. In another embodiment, the matrix fill comprises at oxyl 40 hydrogenated castor oil, polyoxyl 10 oleyl ether, least one or more Sweeteners. In one embodiment, the one or polyoxyl 20 cetostearyl ether, polyoxyl 40 stearate, polysor more Sweeteners comprise mannitol, thaumatin, glycyrrhizic bate 20, polysorbate 40, polysorbate 60, polysorbate 80, acid salt, maltitol. Sucralose, acesulfame salts, Steviol gly diacetate, monostearate, sodium lauryl Sulfate, Sodium Stear cosides (e.g., Stevia(R, Truvia(R), Saccharin, calcium saccha ate, Sorbitan monolaurate, Sorbitan monooleate, Sorbitan rin, sodium saccharin, aspartame, acesulfame potassium, monopalmitate, Sorbitan monostearate, Stearic acid, trola agave nectar, high-fructose corn syrup, honey, dextrates, mine, emulsifying wax); Filtering aids (powdered cellulose, dextrose, excipient dextrose and simple Sugars such as purified siliceous earth); Flavors and perfumes (anethole, glucose, fructose. Sucrose, Sucralose, lactose, or combina benzaldehyde, ethyl vanillin, menthol, methyl salicylate, tions thereof. In one aspect, the Sweeteners comprise one or monosodium glutamate, orange flower oil, peppermint, pep more of mannitol, maltitol (e.g., Lycasin(R), Xylitol. Sucral permint oil, peppermint spirit, rose oil, stronger rose water, ose, thaumatin (e.g., Talin R.), glycyrrhizic acid salts (Mag thymol, tolu balsam tincture, Vanilla, Vanilla tincture, van naSweet(R), or combinations thereof. illin); Humectants (glycerol, hexylene glycol, Sorbitol); 0131. In another embodiment the matrix fill comprises at Plasticizers (e.g., castor oil, diacetylated monoglycerides, least one solvent. In one aspect, the solvent is water. diethyl phthalate, glycerol, mono- and di-acetylated mono 0132) Additional pharmaceutical excipients useful for glycerides, propylene glycol, triacetin, triethylcitrate); Poly capsule shells or matrix fills as described herein include, for mers (e.g., cellulose acetate, alkyl celluloses, hydroxyalkyl, example, the following: Acidifying agents (acetic acid, acrylic polymers and copolymers); Solvents (acetone, alco glacial acetic acid, citric acid, fumaric acid, hydrochloric hol, diluted alcohol, amylene hydrate, benzyl benzoate, acid, diluted hydrochloric acid, malic acid, nitric acid, butyl alcohol, carbon tetrachloride, chloroform, corn oil, phosphoric acid, diluted phosphoric acid, Sulfuric acid, cottonseed oil, ethyl acetate, glycerol, hexylene glycol, tartaric acid); Alkalizing agents (ammonia Solution, ammo isopropyl alcohol, methyl alcohol, methylene chloride, nium carbonate, diethanolamine, diisopropanolamine, methyl isobutyl ketone, mineral oil, peanut oil, propylene US 2016/0279056A1 Sep. 29, 2016

carbonate, Sesame oil, water for injection, Sterile water for the classes of excipients and the particular excipients that injection, sterile water for irrigation, purified water); Sor may be used in oral dosage forms as described herein. bents (powdered cellulose, charcoal, purified siliceous I0133. In one embodiment, one or more hydrophilic earth); Carbon dioxide sorbents (barium hydroxide lime, vehicles comprise about 20% to about 95% by weight of the Soda lime); Stiffening agents (hydrogenated castor oil, ceto matrix fill, including each integer within the specified range. Stearyl alcohol, cetyl alcohol, cetyl esters wax, hard fat, In another embodiment, the one or more hydrophilic paraffin, polyethylene excipient, Stearyl alcohol, emulsify vehicles comprise about 20% to about 50%, about 25% to ing wax, white wax, yellow wax); Suspending and/or vis about 50%, about 30% or about 45%, about 40% to about cosity-increasing agents (acacia, agar, alginic acid, alumi 60%, or about 50% to about 95% by weight of the matrix fill. num monostearate, bentonite, purified bentonite, magma In one aspect, the total hydrophilic vehicle comprises about bentonite, carbomer, carboxymethylcellulose calcium, car 20%, about 25%, about 30%, about 35%, about 40%, about boxymethylcellulose sodium, carboxymethylcellulose 45%, about 50%, about 55%, about 60%, about 65%, about Sodium 12, carrageenan, microcrystalline and carboxymeth 70%, about 75%, about 80%, about 85%, or about 90% by ylcellulose sodium cellulose, dextrin, gelatin, guar gum, weight of the matrix fill. In another aspect, the total hydro hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxy philic vehicle comprises about 40%, about 60%, about or propyl methylcellulose, magnesium aluminum silicate, about 90% by weight of the matrix fill. methylcellulose, pectin, polyethylene oxide, polyvinyl alco I0134. In another embodiment, the hydrophilic vehicle hol, povidone, alginate, silicon dioxide, colloidal silicon comprises polypropylene glycol having a weight percentage dioxide, Sodium alginate, tragacanth, Xanthan gum); Sweet of about 0% to about 20% by weight of the matrix fill, ening agents (aspartame, dextrates, dextrose, excipient dex including each integer within the specified range. In one trose, fructose, mannitol, saccharin, calcium saccharin, embodiment, the polypropylene glycol comprises about 0% Sodium saccharin, Sorbitol, Solution Sorbitol. Sucrose, com to about 15%, about 0% to about 10%, or about 5% to about pressible Sugar, confectioner's Sugar, syrup); Surfactants 10% by weight of the matrix fill. In one aspect, the poly (simethicone); Tablet binders (acacia, alginic acid, sodium propylene glycol comprises about 0%, about 5%, about carboxymethylcellulose, microcrystalline cellulose, dextrin, 10%, about 15%, or about 20% by weight of the matrix fill. ethylcellulose, gelatin, liquid glucose, guar gum, hydroxy In another aspect, polypropylene glycol comprises about 8% propyl methylcellulose, methylcellulose, polyethylene by weight of the shell. In another aspect, the polypropylene oxide, povidone, pregelatinized Starch, syrup); Tablet and/or glycol comprises about 2%, about 6%, about 7%, or about capsule diluents (calcium carbonate, dibasic calcium phos 9% by weight of the fill. phate, tribasic calcium phosphate, calcium Sulfate, microc I0135) In another embodiment, the hydrophilic vehicle rystalline cellulose, powdered cellulose, dextrates, dextrin, comprises polyethylene glycol 400 having a weight percent dextrose excipient, fructose, kaolin, lactose, mannitol, Sor age of about 0.01% to about 50% by weight of the matrix fill, bitol, starch, pregelatinized starch, Sucrose, compressible including each integer within the specified range. In one Sugar, confectioner's Sugar); Tablet disintegrants (alginic embodiment, polyethylene glycol 400 comprises about acid, microcrystalline cellulose, croScarmellose Sodium, 0.01% to about 40%, about 0.1% to about 30%, or about crospovidone, polacrilin potassium, sodium starch glyco 10% to about 30% by weight of the matrix fill. In one aspect, late, starch, pregelatinized starch); Tablet and/or capsule polyethylene glycol 400 comprises about 1%, about 10%, lubricants (calcium Stearate, glyceryl behenate, magnesium about 15%, about 20%, about 25%, about 30%, about 40%, Stearate, light mineral oil, Sodium Stearyl fumarate, Stearic about 45%, or about 50% by weight of the matrix fill. In acid, purified Stearic acid, talc, hydrogenated vegetable oil, another aspect, polyethylene glycol 400 comprises about Zinc Stearate); Thickening agents (gelatin having a Bloom 20% by weight of the fill. In another aspect, polyethylene strength of 50-100); Tonicity agent (dextrose, glycerol, glycol 400 is about 1%, about 16%, about 18%, about 20%, mannitol, potassium chloride, Sodium chloride); Vehicle: about 25%, about 30%, about 45%, or about 50% by weight flavored and/or Sweetened (aromatic elixir, compound ben of the fill. Zaldehyde elixir, iso-alcoholic elixir, peppermint water, Sor 0.136. In another embodiment, the hydrophilic vehicle bitol Solution, syrup, tolu balsam syrup); Vehicle: oleaginous comprises polyvinylpyrrolidone K30 having a weight per (almond oil, corn oil, cottonseed oil, ethyl oleate, isopropyl centage of about 0% to about 2% by weight of the matrix fill, myristate, isopropyl palmitate, mineral oil, light mineral oil, including each integer within the specified range. In one myristyl alcohol, octyl dodecanol, olive oil, peanut oil, embodiment, polyvinylpyrrolidone K30 comprises about persic oil, Sesame oil, soybean oil, squalane); Vehicle: Solid 0.25% to about 1.75%, about 0.50% to about 1.75%, or carrier (sugar spheres); Vehicle: sterile (Bacteriostatic water about 0.75% to about 1.75% by weight of the matrix fill. In for injection, bacteriostatic sodium chloride injection); Vis one aspect, polyvinylpyrrolidone K30 comprises about 0%. cosity-increasing (see Suspending agent); Water repelling about 0.25%, about 0.50%, about 0.75%, about 1%, about agent (cyclomethicone, dimethicone, simethicone); and/or 1.25%, about 1.5%, about 1.75%, or about 2% by weight of solubilizing agent (benzalkonium chloride, benzethonium the matrix fill. In another aspect, polyvinylpyrrolidone K30 chloride, cetylpyridinium chloride, docusate sodium, non comprises about 1.2% by weight of the fill. In another Oxynol 9, nonoxynol 10, octoxynol 9, poloxamer, polyoxyl aspect, polyvinylpyrrolidone K30 comprises about 1%, 35 castor oil, polyoxyl 40, hydrogenated castor oil, polyoxyl about 1.1%, about 1.3%, about 1.4%, about 1.5%, or about 50 stearate, polyoxyl 10 oleyl ether, polyoxyl 20, cetostearyl 1.7% by weight of the fill. ether, polyoxyl 40 stearate, polysorbate 20, polysorbate 40, 0.137 In another embodiment, one or more excipients polysorbate 60, polysorbate 80, sodium lauryl sulfate, sor comprise about 0.1% to about 25% by weight of the matrix bitan monolaurate, Sorbitan monooleate, Sorbitan mono fill, including each integer within the specified range. In one palmitate, Sorbitan monostearate, tyloxapol). This list is not embodiment, the one or more excipients comprise about meant to be exclusive, but instead merely representative of 0.1% to about 10%, about 10% to about 25%, or about 5% US 2016/0279056A1 Sep. 29, 2016 to about 15% by weight of matrix fill. In one aspect, the one about 5% by weight of the matrix fill, including each integer or more excipients comprise about 0.1%, 1%, about 5%, within the specified range. In one embodiment, acesulfame about 10%, about 15%, about 20%, or about 25%, by weight potassium comprises about 0.1% to about 4%, about 0.2% to of the matrix fill. In one aspect, the one or more excipients about 3%, or about 0.3% to about 2% by weight of the comprise about 10% by weight of the fill. In another aspect, matrix fill. In one aspect, acesulfame potassium comprises the one or more excipients comprise about 1%, about 2%, about 0%, about 1%, about 2%, about 3%, about 4%, or about 2.5%, about 3%, about 4%, about 5%, about 10%, about 5% by weight of the matrix fill. In another aspect, about 15%, or about 20% by weight of the fill. acesulfame potassium comprises about 0.6% by weight of 0138. In another embodiment, one or more sweeteners the fill. In another aspect, acesulfame potassium comprises comprise about 0.1% to about 20% by weight of the matrix about 0.3%, about 0.5%, or about 0.9% by weight of the fill. fill, including each integer within the specified range. In one 0143. In another embodiment, the sweeteners comprise a embodiment, the one or more Sweeteners comprises about glycyrrhizic acid salt having a weight percentage of about 0.1% to about 15%, about 0.1% to about 10%, or about 0.1% 0% to about 5% by weight of the matrix fill, including each to about 5% by weight of the matrix fill. In one aspect, the integer within the specified range. In one embodiment, the one or more sweeteners comprises about 0.1%, about 0.15%, glycyrrhizic acid salt comprises about 0.1% to about 4%, about 0.2%, about 0.25%, about 0.3%, about 0.35%, about about 0.2% to about 3%, or about 0.3% to about 2% by 0.4%, about 0.45%, about 0.5%, about 0.55%, about 0.6%, weight of the matrix fill. In one aspect, the glycyrrhizic acid about 0.65%, about 0.7%, about 0.75%, about 0.8%, about salt comprises about 0%, about 1%, about 2%, about 3%, 0.85%, about 0.9%, about 0.95%, or about 1% by weight of about 4%, or about 5% by weight of the matrix fill. In the matrix fill. In one aspect, the one or more Sweeteners another aspect, the glycyrrhizic acid salt comprises about comprises about 1%, about 2%, about 3%, about 4%, about 0.5% by weight of the fill. In another aspect, the glycyrrhizic 5%, about 6%, about 7%, about 8%, about 9%, about 10%, acid salt comprises about 0.3%, about 0.6%, or about 0.9% about 12%, or about 15% by weight of the matrix fill. In one by weight of the fill. aspect, the one or more sweeteners comprise about 0.5% by 0144. In one embodiment, one or more flavorings com weight of the matrix fill. In another aspect, the one or more prise about 0.1% to about 5% by weight of the matrix fill, sweeteners comprise about 0.2%, about 0.3%, about 0.4%, including each integer within the specified range. In another or about 0.7% by weight of the fill. embodiment, the one or more flavorings comprise about 0139. In another embodiment, the one or more sweeten 0.1% to about 4.5%, about 0.1% to about 3.5%, or about ers comprise sucralose having a weight percentage of about 0.1% to about 3% by weight of the matrix fill. In one aspect, 0% to about 2% by weight of the matrix fill, including each the flavorings comprise about 0.01, about 1%, about 1.5%, integer within the specified range. In another embodiment, about 1.6%, about 2.0%, about 2.5%, about 3%, about 3.5%, sucralose comprises about 0.1% to about 1.74%, about 0.2% about 4%, about 4.5%, about 5%, about 5.5%, or about 6% to about 1.5%, about 0.3% to about 1.5%, or about 0.4% to by weight of the matrix fill. In another aspect, the flavorings about 1% by weight of the matrix fill. In one aspect, comprise about 4% by weight of the fill. In another aspect, sucralose comprises about 0%, about 0.25%, about 0.5%, the flavorings comprise about 0.01%, about 0.09%, about about 0.75%, about 1%, about 1.25%, about 1.5%; about 1%, about %, or about 5% by weight of the fill. 1.75%, or about 2% by weight of the matrix fill. In another 0145. In another embodiment, the flavorings comprise aspect, sucralose comprises about 0.6% by weight of the fill. citric acid having a weight percentage of about 0.01% to In another aspect, Sucralose comprises about 0.5%, about about 3% by weight of the matrix fill, including each integer 0.55%, or about 0.65% by weight of the fill. within the specified range. In one embodiment, citric acid 0140. In one embodiment, the Sweeteners comprise man comprises about 0.25% to about 2.75%, about 0.5% to about nitol having a weight percentage of about 0% to about 5% 2.5%, or about 0.75% to about 2.25% by weight of the by weight of the matrix fill, including each integer within the matrix fill. In one aspect, citric acid comprises about 0%. specified range. In one embodiment, mannitol comprises about 0.5%, about 1%, about 1.5%, about 2%, about 2.5%, about 0.1% to about 4%, about 0.2% to about 3%, or about or about 3% by weight of the matrix fill. In another aspect, 0.3% to about 2% by weight of the matrix fill. In one aspect, citric acid comprises about 1% by weight of the fill. In mannitol comprises about 0%, about 1%, about 2%, about another aspect, citric acid comprises about 0.5%, about 3%, about 4%, or about 5% by weight of the matrix fill. In 0.75%, about 1.25%, or about 1.5% by weight of the fill. another aspect, mannitol comprises about 0.5% by weight of 0146 In another embodiment, the flavorings comprise the fill. In another aspect, mannitol comprises about 0.3%, lactic acid having a weight percentage of about 0% to about about 0.6%, or about 0.9% by weight of the fill. 3% by weight of the matrix fill, including each integer 0141. In another embodiment, the sweeteners comprise within the specified range. In one embodiment, lactic acid thaumatin at a weight percentage of about 0% to about 5% comprises about 0.25% to about 2.75%, about 0.5% to about by weight of the matrix fill, including each integer within the 2.5%, or about 0.75% to about 2.25% by weight of the specified range. In one embodiment, thaumatin comprises matrix fill. In one aspect, lactic acid comprises about 0%. about 0.1% to about 4%, about 0.2% to about 3%, or about about 0.5%, about 1%, about 1.5%, about 2%, about 2.5%, 0.3% to about 2% by weight of the matrix fill. In one aspect, or about 3% by weight of the matrix fill. In another aspect, thaumatin comprises about 0%, about 1%, about 2%, about lactic acid comprises about 1% by weight of the fill. In 3%, about 4%, or about 5% by weight of the matrix fill. In another aspect, lactic acid comprises about 0.5%, about another aspect, thaumatin comprises about 0.5% by weight 0.75%, about 1.25%, or about 1.5% by weight of the fill. of the fill. In another aspect, thaumatin comprises about 0.147. In one embodiment, the flavorings comprise 0.3%, about 0.6%, or about 0.9% by weight of the fill. Sodium citrate having a weight percentage of about 0% to 0142. In another embodiment, the sweeteners comprise about 3% by weight of the matrix fill, including each integer acesulfame potassium at a weight percentage of about 0% to within the specified range. In another embodiment, sodium US 2016/0279056A1 Sep. 29, 2016

citrate comprises about 0.25% to about 2.75%, about 0.5% betapentane, chlophedianol, clobutinol, clofedanol, clop to about 2.5%, or about 0.75% to about 2.25% by weight of erastine, codeine, dextromethorphan, diacetylmorphine, the matrix fill. In one aspect, Sodium citrate comprises about dibunate, dihydrocodeine, dimemorfan, dimethoxanate, 0%, about 0.5%, about 1%, about 1.5%, about 2%, about diphenhydramine, dropropizine, droxypropine, ethylmor 2.5%, or about 3% by weight of the matrix fill. In another phine, fedrilate, glaucine, hydrocodone, hydromorphone, aspect, sodium citrate comprises about 1% by weight of the isoaminile, laudanum, levodropropizine, levomethadone, fill. In another aspect, sodium citrate comprises about 0.5%; levopropoxyphene, meprotixol, methadone, morclofone, about 0.75%, about 1.25%, or about 1.5% by weight of the nepinalone, nicocodine, nicodicodine, normethadone, fill. noscapine, oxeladin, oxolamine, pentoxyverine, pholcodine, 0148. In another embodiment, a solvent comprises about pipaZetate, piperidione, prenoXdiazine, tipepidine, Zipeprol, 0% to about 15% by weight of the matrix fill, including each acetylcysteine, althea root, ambroXol, antimony pentasul integer within the specified range. In another embodiment, fide, bromhexine, carbocisteine, cineole, combinations, the solvent comprises about 0.5% to about 13%, about 1% combinations, creosote, dembrexine hydrochloride, domi to about 11%, about 1.5% to about 9%, or about 2% to about odol, dornase alfa, eprazinone, erdosteine, guaiacolsul 6% by weight of the matrix fill. In another aspect, the solvent fonate, guaifenesin, hederae helicis folium, ipecacuanha, comprises about 0%, about 5%, about 10%, or about 15% by letosteine, levo Verbenone, mannitol, mesna, neltenexine, weight of the matrix fill. In another aspect, the solvent potassium iodide, Senega, Sobrerol, Stepronin, tiopronin, comprises about 5.5% by weight of the matrix fill. In another tyloxapol, or combinations thereof. In one aspect, the active aspect, the solvent comprises about 4.5%, about 5%, about pharmaceutical ingredient comprises one or more of dex 6%, or about 6.5% by weight of the matrix fill. tromethorphan hydrobromide, menthol, or combinations 0149. In another embodiment, the solvent comprises thereof. water at a weight percentage of about 0% to about 15% by 0153. In one embodiment described herein, the active weight of the matrix fill, including each integer within the pharmaceutical ingredient is an anti-allergy agent. Exem specified range. In one embodiment, water comprises about plary anti-allergy agents include pseudoephedrine, cetiriz 0.5% to about 13%, about 1% to about 11%, about 1.5% to ine, loratadine, feXofenadine, diphenhydramine, levocetiriz about 9%, or about 2% to about 6% by weight of the matrix ine, desloratadine, or combinations thereof. fill. In another aspect, water comprises about 0%, about 5%, 0154. In one embodiment described herein, the active about 10%, or about 15% by weight of the matrix fill. In pharmaceutical ingredient is an oral rinsing agent. Exem another aspect, water comprises 5.5% by weight of the plary oral rinsing agents include phenol, ethanol, thymol. matrix fill. In another aspect, water comprises about 4.5%, eucalyptol, ethanol, methyl salicylate, chlorhexidine glucon about 5%, about 6%, or about 6.5% by weight of the matrix ate, cetylpyridinium chloride, hexetidine, triclosan, hydro fill. gen peroxide, domiphen bromide, or combinations thereof. 0150. In another embodiment, the shell comprises one or In one embodiment described herein, the active pharmaceu more colorings. Typical food colorings Such as FD&C food tical ingredient comprises an oral rinsing agent comprising dyes or D&C dyes can be used in any combinations to create one or more of ethanol (about 20% to about 30%) menthol the desired color. Dyes can be used in weight percentages (0.042%), thymol (0.064%), methyl salicylate (0.06%), and from 0.0001% to 0.5%, including all integers and fractions eucalyptol (0.092%). within the specified ranges. 0.155. In one embodiment described herein, the active 0151. In one embodiment described herein, the compo pharmaceutical ingredient is an antidiarrheal or antacid sitions described herein comprise one or more active phar comprising bismuth Subsalicylate, loperamide hydrochlo maceutical ingredients. In one embodiment, one active phar ride, aluminum hydroxide, magnesium hydroxide, Simethi maceutical ingredient is the only active ingredient in the cone, aluminum carbonate, calcium carbonate, sodium pharmaceutical composition. In another embodiment, one or bicarbonate, magnesium aluminum silicate, hydrotalcite, more active pharmaceutical ingredients or drugs are magaldrate, cimetidine, famotidine, nizatidine, ranitidine, included in the pharmaceutical composition. In another lansoprazole, omeprazole, esomeprazole, rabeprazole, pan embodiment, the active pharmaceutical ingredient can be an toprazole, dexlansoprazole, or combinations thereof. In one active pharmaceutical ingredient, a derivative thereof, or embodiment described herein, the active pharmaceutical combinations thereof. ingredient comprises one or more of bismuth Subsalicylate 0152. In one embodiment, the compositions described (~17.6 mg), benzoic acid, D&C Red No. 22, D&C Red No. herein comprise one or more active pharmaceutical ingre 28, flavoring, magnesium aluminum silicate, methylcellu dients useful for treating, retarding the progression of lose, Sodium saccharin, Salicylic acid, Sodium salicylate, delaying the onset of prophylaxis of amelioration of, or Sorbic acid, and water. reducing the symptoms of pain, inflammation, fever, or 0156. In another embodiment, the active pharmaceutical symptoms Stemming from cough or cold. In one embodi ingredient is an irritable bowel syndrome therapeutic. Exem ment described herein, the active pharmaceutical ingredient plary non-limiting active pharmaceutical ingredients useful comprises one or more of astemizole, azelastine, azatadine, for the treatment of irritable bowel syndrome comprise brompheniramine, carbinoxamine, cetirizine, chlorpheni antidiarrheals such as atropine, diphenoxylate (Lomotil.R.), ramine, clemastine, cyproheptadine, desloratadine, dexbro dicyclomine (Bentyl(R), loperamide (Imodium(R), rifaximin mpheniramine, dexchlorpheniramine, diphenhydramine, (Xifaxan R), alosetron (LotronexR); bile acid binding agents fexofenadine, hydroxy Zine, levocetirizine, loratadine, phen such as cholestyramine (PrevailiteR); constipation therapeu indamine, pheniramine, phenyltoloxamine, promethazine, tics such as linaclotide (Linzess(R) or lubiprostone (Amitiza) pyrilamine, terfenadine, tripelennamine, triprolidine, acetyl or combinations thereof. dihydrocodeine, benproperine, benzonatate, benzylmor 0157. In one embodiment described herein, the active phine, bibenzonium bromide, butamirate, butorphanol, car pharmaceutical ingredient is a constipation therapeutic Such US 2016/0279056A1 Sep. 29, 2016

as linaclotide (Linzess(R) or lubiprostone (Amitiza (R), meth 0166 In one embodiment, the active pharmaceutical ylcellulose, polycarbophil, psyllium, mineral oil, glycerol, ingredient is an effervescent including but not limited to docusate sodium, sodium bicarbonate, Sodium phosphate, Sodium bicarbonate, citric acid, tartaric acid, or combina magnesium citrate, magnesium oxide, magnesium sulfate, tions thereof. Effervescent may be combined with one or bisacodyl, Sennosides, Senna, castor oil or combinations more cold, cough, allergy, nasal decongestant, antitussive, thereof. expectorant, antihistamine, stimulant, sedative, anti-inflam 0158. In another embodiment described herein, the active matory, antibiotic, anti-viral, anti-asthmatic, anti-migraine, pharmaceutical ingredient comprises one or more corticos hypnotic, narcotic analgesic, or narcotic antagonist active teroids for treating inflammatory diseases and conditions pharmaceutical ingredients, or further combinations thereof. and inflammation of the gastrointestinal tract, including but (0167. In one embodiment described herein, the active not limited to esophageal inflammation. In one embodiment pharmaceutical ingredient is one or more non-steroidal described herein, the active pharmaceutical ingredient com anti-inflammatory drugs (NSAID). Non-limiting examples prises one or more corticosteroids including but not limited of NSAID active pharmaceutical ingredients comprise aspi to alclometasone, amcinonide, beclometaSone, betametha rin, ibuprofen, aceclofenac, acemetacin, aloxiprin, azapro Sone, budesonide, ciclesonide, clobetasol, clobetaSone, clo paZone, benorilate, bromfenac, carprofen, celecoxib, choline cortolone, cloprednol, cortivaZol, deflazacort, deoxycorti magnesium salicylate, diclofenac, diflunisal, etodolac, etori costerone, desonide desoximetasone, dexamethasone, coxib, faislamine, fenbufen, fenoprofen, flurbiprofen, indo diflorasone, diflucortolone, difluprednate, fluclorolone, metacin, ketoprofen, ketorolac, lornoxicam, loxoprofen, fludrocortisone, fludroxycortide, flumetasone, flunisolide, meloxicam, meclofenamic acid, mefenamic acid, meloxi fluocinolone acetonide, fluocinonide, fluocortin, fluocor cam, metamizole, methyl salicylate, magnesium salicylate, tolone, fluorometholone, fluperolone, fluticaSone, flutica nabumetone, naproxen, nimeSulide, oxyphenbutaZone, par Sone propionate, fluprednidene, formocortal, halcinonide, acetamol, parecoxib, phenylbutaZone, piroxicam, salicyl halometaSone, hydrocortisone aceponate, hydrocortisone salicylate, Sulindac, Sulfinpyrazone, Suprofen, tenoxicam, buteprate, hydrocortisone butyrate, loteprednol, medrysone, tiaprofenic acid, tolmetin, Valdecoxib, or combinations meprednisone, methylprednisolone, methylprednisolone thereof. aceponate, mometasone furoate, paramethasone, prednicar 0.168. In another embodiment, suitable active pharmaceu bate, prednisone, prednisolone, prednylidene, rimexolone, tical ingredients can comprise analgesics, such as, for tiXocortol, triamcinolone, ulobetasol, combinations thereof, example: acetylsalicylic acid, aloxiprin, aminophenaZone, or pharmaceutically acceptable salts, or esters thereof. anilides, benorilate, benzomorphan derivatives, bezitramide, 0159. In another embodiment described herein, the active bucetin, buprenorphine, butorphanol, carbasalate calcium, pharmaceutical ingredient comprises one or more of 5-fluo choline Salicylate, codeine, dextromoramide, dextro rouracil, 5-fluorodeoxyuridine, capecitabine, derivatives propoxyphene, dezocine, diamorphine, diflunisal, dihydro thereof, or combinations thereof for treating neoplasia, codeine, dihydrocodone, dihydromorphine, diphenylpro including but not limited to head and neck neoplasia. pylamine derivatives, dipyrocetyl, ethenZamide, fentanyl. 0160. In another embodiment described herein, the active floctafenine, flupirtine, glafenine, guacetisal, hydrocodone, pharmaceutical ingredient comprises one or more of calcium hydrocodone bitartrate, hydromorphone, hydromorphone Supplements or calcimimetics including but not limited to hydrochloride, imidazole salicylate, ketobemidone, metam cinacalcet, derivatives thereof, or combinations thereof for izole sodium, methadone, morphinan derivatives, morphine, treating hyperthyroidism, hypercalcemia, hyperparathyroid morphine Sulphate pentahydrate, morphine-6-glucuronode, ism, parathyroid carcinoma, or a combination thereof. morpholine Salicylate, nalbuphine, natural opium alkaloids, 0161 In some embodiments, the active pharmaceutical nefopam, nicomorphine, nifenaZone, norhydrocodone, ingredient is a sleep aid. Examples of sleep aids include, but noroxycodone, opioids, opium, oripavine derivatives, oxy are not limited to doxylamine, diphenhydramine hydrochlo codeine, oxycodone, oxycodone hydrochloride, oxymor ride, melatonin, 1-theanine, or combinations thereof. phone, papaveretum, pentazocine, pethidine, phenacetin, 0162. In some embodiments, the active pharmaceutical phenazocine, phenaZone, phenylpiperidine derivatives, pir ingredient is an oral saliva Substitute. Such as, for example: itramide, potassium salicylate, propacetamol, propy monofluorophosphate, lactoferrin, lysozyme, lactoperoxi phenaZone, pyrazolones, rimazolium, Salicylamide, Salicylic dase, glucose oxidase, mutanase, dextranase, glycerol, or acid derivatives, Salsalate, sodium salicylate, tapentadol, combinations thereof. tilidine, tramadol, Viminol, Ziconotide, or combinations 0163. In some embodiments, the active pharmaceutical thereof. ingredient is a teeth-bleaching or teeth-whitening agent, 0169. In another embodiment, the active pharmaceutical including but not limited to carbamide peroxide, sodium ingredient disclosed herein includes an opioid, the opioid is bicarbonate, hydrated silica, silicon dioxide, polyvinylpyr selected from buprenorphine, codeine, dextromoramide, rolidone, potassium nitrate, sodium monofluorophosphate, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, Sodium tripolyphosphate, strontium chloride, or combina morphine, pentazocine, oxycodeine, oxycodone, oxymor tions thereof. phone, norhydrocodone, noroxycodone, morphine-6-glu 0164. In another embodiment, the active pharmaceutical curonode, tramadol, tapentadol, dihydromorphine, or com ingredient is a tooth enamel-enhancing agent. Exemplary binations thereof. tooth enamel enhancing agents include potassium nitrate, (0170. In one embodiment described herein, the active strontium acetate, strontium chloride, calcium sodium phos pharmaceutical ingredient is a probiotic. Exemplary probi phosilicate, or combinations thereof. otics include Bifidobacterium infantis 35624, Bifidobacte 0.165. In another embodiment, the active pharmaceutical rium lactis HNO19, Lactobacillus reuteri ATCC55730, Lac ingredient is an oral anesthetic, including but not limited to tobacillus rhamnosus, Lactobacillus casei DN-114 001, benzocaine, lidocaine, clove oil, or combinations thereof. Bifidobacterium lactis Bb-12 or combinations thereof. US 2016/0279056A1 Sep. 29, 2016 20

0171 In another embodiment, the active pharmaceutical biloba, ginger, cat's claw, hypericum, aloe Vera, evening ingredient comprises active drug Substances used in the primrose, garlic, ginseng, Capsicum, dong quai, ginseng, treatment of addictive disorders, such as, for example: feverfew, fenugreek, echinacea, green tea, marshmallow, nicotine, nicotine polacrilex, bupropion, Varenicline, disul saw palmetto, tea tree oil, fish oil, psyllium, kava-kava, firam, calcium carbimide, acamprosate, naltrexone, licorice root, mahonia aquifolium, hawthorne, tumeric, buprenorphine, methadone, levacetylmethadol, lofexidine, witch hazel, yohimbe, aleurain, mistletoe, bilberry, bee betahistine, cinnarizine, flunarizine, acetylleucine, ganglio pollen, peppermint oil, beta-carotene, genistein, lutein, lyco sides, ganglioside derivatives, tirilazad, riluzole, Xaliproden, pene, polyphenols, and the like. Further examples of suitable hydroxybutyric acid, amifampiridine, or combinations nutraceuticals include those listed in Handbook of Nutra thereof. In one embodiment described herein, the active ceuticals and Functional Foods, Robert E. C. Wildman, Ed., pharmaceutical ingredient comprises one or more of nicotine CRC Press (2001), which is incorporated by reference (~2 mg), acesulfame potassium, magnesium oxide, menthol, herein for the teachings related to nutraceuticals. peppermint oil, Xylitol, Sodium bicarbonate, sodium carbon 0.175. In another embodiment, the active pharmaceutical ate, or combinations thereof. ingredients described herein may comprise pharmaceuti 0172. In another embodiment, the active pharmaceutical cally acceptable salts of any of the above mentioned active ingredient can comprise those found in energy drinks, drug Substances. The term “pharmaceutically acceptable including caffeine, taurine, ginko biloba, glucuronolactone, salts' of an active pharmaceutical ingredient includes alkali inositol, niacin, niacinamide, D-pantothenol, panax ginseng metal salts such as, for example, Sodium or potassium salts, root extract, pyridoxine HCl, vitamin B12, cyanocobalamin, alkaline earth metal salts such as, for example, calcium and riboflavin, guarana, L-carnitine, or combinations thereof. magnesium salts, and salts with organic or inorganic acid 0173. In another embodiment, the pharmaceutical com Such as, for example, hydrochloric acid, hydrobromic acid, position can comprise vitamins or minerals. “Vitamins' as nitric acid, Sulfuric acid, phosphoric acid, citric acid, formic used herein refers to nutraceuticals or pharmaceutical ingre acid, maleic acid, Succinic acid, tartaric acid, methanesul dients comprising organic Substances that are typically con phonic acid, toluenesulphonic acid etc. In another embodi sidered essential for the normal growth and activity of a ment, the active pharmaceutical ingredient may also be in Subject (e.g., a human or non-human animal patient to whom the form of pharmaceutically acceptable salts, uncharged or the composition is to be administered). Non-limiting charged molecules, molecular complexes, Solvates, or anhy examples of vitamins include, but are not limited to vitamin drates thereof, and, if relevant, single isomers, enantiomers, A (retinol), B1 (thiamine), B2 (riboflavin), B complex, B6 racemic mixtures, or mixtures thereof. (pyridoxine), B12 (cobalamin), C (ascorbic acid), D (cho 0176). In another embodiment, the active pharmaceutical lecalciferol), E (tocopherol), F (linoleic acid), G, H (biotin), ingredient may be in any of its crystalline, polymorphous, and K, and choline, folic acid, inositol, niacin, pantothenic semi-crystalline, amorphous or polyamorphous forms or acid, para-aminobenzoic acid or combinations thereof. mixtures thereof. 0.174. In some embodiments, the active pharmaceutical 0177. In another embodiment, an active pharmaceutical ingredient is a pharmaceutical a nutraceutical. Examples of ingredient comprises about 0% to about 6% by weight of the nutraceuticals include, but are not limited to, amino acids, matrix fill, including each integer within the specified range. terpenoids (e.g., carotenoid terpenoids and non-carotenoid In another embodiment, the active pharmaceutical ingredi terpenoids), herbal Supplements, homeopathic Supplements, ent comprises about 0.25% to about 5%, about 0.5% to about glandular supplements, polyphenolics, flavonoid polyphe 4%, about 0.75% to about 3%, or about 1% to about 2% by nolics, phenolic acids, curcumin, resveratrol, lignans, glu weight of the matrix fill. In one aspect, the active pharma cosinolates, isothiocyanates, indoles, thiosulfinates, phytos ceutical ingredient comprises about 0%, about 1%, about terols, anthraquinones, capsaicin, piperine, chlorophyll. 2%, about 3%, about 4%, about 5%, or about 6% by weight betaine, oxalic acid, acetyl-L-carnitine, allantoin, andros of the matrix fill. In one aspect, the active pharmaceutical tenediol, androstendione, betaine (trimethylglycine), caf ingredient comprises about 1.6% by weight of the fill. In one feine, calcium pyruvate (pyruvic acid), carnitine, carnosine, aspect, the active pharmaceutical ingredient comprises about carotene, carotenoid, choline, chlorogenic acid, cholic acid, 1%, about 1.5%, about 2%, or about 2.5% by weight of the chondroitin Sulfate, chondroitin Sulfate, cholestan, chrysin, fill. coenzyme Q10, conjugated linoleic acid, corosolic acid, 0178. In another embodiment, the active pharmaceutical creatine, dehydroepiandrosterone, dichlorophen, diindo ingredient comprises dextromethorphan hydrobromide hav lymethane, dimethylglycine, dimercapto Succinic acid, ing a weight percentage of about 0% to about 5% by weight ebselen, ellagic acid, enzymes, fisetin, formononetin, glu of the matrix fill, including each integer within the specified caric acid (glucarate), glucosamine (HCl or Sulfate), glu range. In one aspect, dextromethorphan hydrobromide com cosamine (N-acetyl), glutathione, hesperidine, hydroxy-3- prises about 0.25% to about 5%, about 0.5% to about 4%, methylbutyric acid, 5-hydroxytryptophan, indole-3- about 0.75% to about 3%, or about 0.75% to about 2% by carbinol, inositol, isothiocyanates, linolenic acid-gamma, weight of the matrix fill. In another aspect, dextrometho lipoic acid (alpha), melatonin, methylsulfonylmethane, min rphan hydrobromide comprises about 0%, about 1%, about erals, maringin, pancreatin, para-aminobenzoic acid, paraben 2%, about 3%, about 4%, or about 5% by weight of the (methyl or propyl), phenolics, phosphatidylcholine, phos matrix fill. In one aspect, dextromethorphan hydrobromide phatidylserine, phospholipids, phytosterols, progesterone, comprises about 1% by weight of the fill. In one aspect, pregnenolone, omega-3 fatty acids, quercetin, resveratrol, dextromethorphan hydrobromide comprises about 0.50%, D-ribose, rutin, S-adenosylmethionine, Salicylic acid, Sul about 0.74%, or about 1.25% by weight of the matrix fill. foraphane, tartaric acid, taxifolin, tetrahydropalmatine, the 0179. In another embodiment, the active pharmaceutical ophyline, theobromine, tigogenin, troXerutin, tryptophan, ingredient comprises menthol at a weight percentage of tocotrienol (alpha, beta, and gamma), Zeaxanthin, gingko about 0% to about 2% by weight of the matrix fill, including US 2016/0279056A1 Sep. 29, 2016

each integer within the specified range. In one aspect, fill mass is about 600 mg. In another aspect, the total mass menthol comprises about 0.1% to about 1.75%, about 0.2% of the matrix fill mass is about 700 mg. In another aspect, the to about 1.5%, about 0.3% to about 1.25%, or about 0.4% to total mass of the matrix fill mass is about 800 mg. In another about 1% by weight of the matrix fill. In another aspect, aspect, the total mass of the matrix fill mass is about 900 mg. menthol comprises about 0%, about 0.25%, about 0.5%, In another aspect, the total mass of the matrix fill mass is about 0.75%, about 1.25%, about 1.5%; about 1.75%; or about 1000 mg. In another aspect, the total mass of the about 2% by weight of the matrix fill. In one aspect, menthol matrix fill mass is about 1100 mg. In another aspect, the total comprises about 0.5% by weight of the fill. In one aspect, mass of the matrix fill mass is about 1200 mg. In another menthol comprises about 0.40%, about 0.45%, about 0.55% aspect, the total mass of the matrix fill mass is about 1300 or about 0.6% by weight of the fill. mg. In another aspect, the total mass of the matrix fill mass 0180. In another embodiment, the ratio of the active is about 1400 mg. In another aspect, the total mass of the pharmaceutical ingredient to the remaining fill components matrix fill mass is about 1500 mg. In another aspect, the total in the matrix fill comprises about 1:10 to about 1:100, mass of the matrix fill mass is about 1600 mg. including each ratio within the specified range. In one embodiment, the ratio of active pharmaceutical ingredient to TABLE 3 the remaining fill components in the fill is about 1:20 to about 1:80, about 1:30 to about 1:70, or about 1:40 to about Exemplary Liquisoft Composition 1:70. In one aspect, the ratio of active pharmaceutical Weight ingredient to the remaining fill components in the matrix fill Percentage is about 1:10, about 1:20, about 1:30, about 1:40, about 1:50, Component Exemplary Component (%) about 1:60, about 1:70, about 1:80, about 1:90, or about Capsule Shell Formulation 1:100. In another aspect, the ratio of active pharmaceutical ingredient to the remaining fill components in the fill is Polymers Gelatin, 150 Bloom 19.3 Gelatin, 100 Blom 8.3 about 1:63. In another aspect, the ratio of active pharma Hydrolyzed Collagen 4.9 ceutical ingredient to the remaining fill components in the Plasticizers Maltitol 16.8 matrix fill is about 1:60, about 1:62, about 1:64, or about Glycerol 24 1:65. Xylitol 2.6 Sweetener(s) Sucralose O.2 0181. In another embodiment, the ratio of the active Polymer Citric Acid O.S pharmaceutical ingredient to the total hydrophilic vehicle in Modifiers the matrix fill comprises about 1:10 to about 1:50, including Coloring FD&C Food colorings O.1 each ratio within the specified range. In one embodiment, Solvent Water 23 the ratio of active pharmaceutical ingredient to the total TOTAL 100% hydrophilic vehicle in the matrix fill comprises about 1:15 to Matrix Fill Formulation about 1:45, or about 1:20 to about 1:40. In one aspect, the Hydrophilic Propylene Glycol 8.O ratio of active pharmaceutical ingredient to the total hydro Vehicles Polyethylene Glycol 400 19.5 philic vehicle is about 1:10, about 1:20, about 1:30, about Polyvinylpyrrollidone K30 1.2 1:40, or about 1:50. In another aspect, the ratio of active Flavorings Citric Acid 1.O pharmaceutical ingredient to the total hydrophilic vehicle in Lactic Acid 1.O Sodium Citrate the matrix fill is about 1:24. In another aspect, the ratio of Orange Flavor PB72 1.6 active pharmaceutical ingredient to the total hydrophilic Sweeteners Mannitol vehicle in the matrix fill is about 1:20, about 1:21, about Acesulfame potassium O.6 1:22, about 1:23, about 1:25, or about 1:26. Glycyrrhizic acid salts (MagnaSweet (R) 0182. In another embodiment, the ratio of the active Maltitol 55.1 pharmaceutical ingredient to the propylene glycol in the Sucralose O.6 matrix fill comprises about 1:1 to about 1:10, including each Excipients e.g., Y-cyclodextrin 2.2 Solvent Water 7.5 ratio within the specified range. In one embodiment, the Active Dextromethorphan 1.6 ratio active pharmaceutical ingredient to propylene glycol in Pharmaceutical Hydrobromide the fill is about 1:1 to about 1:9, about 1:2 to about 1:8, about Ingredients Menthol O.1 1:4 to about 1:7, or about 1:5 to about 1:6. In one aspect, the (API) ratio of active pharmaceutical ingredient to propylene glycol in the matrix fill is about 1:1, about 1:2, about 1:3, about 1:4, TOTAL 100% about 1:5, or about 1:6. In another aspect, the ratio of active pharmaceutical ingredient to propylene glycol in the fill is 0.184 One embodiment described herein is an oral phar about 1:5. In another aspect, the ratio of active pharmaceu maceutical composition Suitable for chewing, Sucking, or tical ingredient to propylene glycol in the matrix is about buccal dissolution comprising the composition in Table 3. 1:2, about 1:3, about 1:4, or about 1:6. 0185. In one embodiment, the pharmaceutical composi 0183. In another embodiment described herein, the total tion described herein, comprises an active pharmaceutical mass of the matrix fill of the pharmaceutical composition ingredient of about 0.5 mg to about 5000 mg, including each described herein that comprises an active pharmaceutical integer within the specified range. ingredient described herein is from about 400 mg to about 0186. In one embodiment, the pharmaceutical composi 1600 mg, including all integers within the specified range. In tion described herein, comprises an active pharmaceutical one aspect, the total mass of the matrix fill mass is about 400 ingredient of about 0.5 mg, about 0.75 mg, about 1 mg, mg. In another aspect, the total mass of the matrix fill mass about 1.25 mg, about 1.5 mg, about 1.75 mg, about 2 mg, is about 500 mg. In one aspect, the total mass of the matrix about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3 mg, US 2016/0279056A1 Sep. 29, 2016 22 about 3.25 mg, about 3.5 mg, about 3.75 mg, about 4 mg. administered, for example, for 1, 2, 3, 4, 5, 6, 7 days, or even about 4.25 mg, about 4.5 mg, about 4.75 mg, about 5 mg. longer. One or more dosage forms can be administered, for about 5.25 mg, about 5.5 mg, about 5.75 mg, about 6 mg, example, for 1, 2, 3, 4 weeks, or even longer. One or more about 6.25 mg, about 6.5 mg, about 6.75 mg, about 7 mg, dosage forms can be administered, for example, for 1, 2, 3, about 7.25 mg, about 7.5 mg, about 7.75 mg, about 8 mg, 4, 5, 6, 7, 8, 9, 10, 11, 12 months, or even longer. One or about 8.25 mg, about 8.5 mg, about 8.75 mg, about 9 mg, more dosage forms can be administered until the patient, about 9.25 mg, about 9.5 mg, about 9.75 mg, or about 10 mg. Subject, mammal, mammal in need thereof, human, or or even greater. human in need thereof, does not require treatment, prophy 0187. In another embodiment described herein, the phar laxis, or amelioration of any disease or condition Such as, for maceutical composition described herein, comprises an example, pain. In some aspects, the dosage form may be active pharmaceutical ingredient of about 10 mg, about 20 co-administered with other pharmaceutical compositions mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg. until the patient, Subject, mammal, mammal in need thereof, about 70 mg, about 80 mg, about 90 mg, about 100 mg. human, or human in need thereof, does not require treat about 110 mg, about 120 mg, about 130 mg, about 140 mg. ment, prophylaxis, or amelioration of any disease or condi about 150 mg, about 160 mg, about 170 mg, about 180 mg. tion including but not limited to pain or illness. about 190 mg, about 200 mg, about 210 mg, about 220 mg. 0190. In one embodiment described herein, the active about 230 mg, about 240 mg, about 250 mg, about 260 mg. pharmaceutical ingredient comprises dextromethorphan about 270 mg, about 280 mg, about 290 mg, about 300 mg. hydrobromide having a dose of about 5 mg to about 200 mg. about 310 mg, about 320 mg, about 330 mg, about 340 mg. including all integers within the specified range. In one about 350 mg, about 360 mg, about 370 mg, about 380 mg. aspect, the dose of dextromethorphan hydrobromide is about about 390 mg, about 400 mg, about 410 mg, about 420 mg. 5 mg. In one aspect, the dose of dextromethorphan hydro about 430 mg, about 440 mg, about 450 mg, about 460 mg. bromide is about 10 mg. In another aspect, the dose of about 470 mg, about 480 mg, about 490 mg, about 500 mg. dextromethorphan hydrobromide is about 15 mg. In another about 510 mg, about 520 mg, about 530 mg, about 540 mg. aspect, the dose of dextromethorphan hydrobromide is about about 550 mg, about 560 mg, about 570 mg, about 580 mg. 20 mg. In another aspect, the dose of dextromethorphan about 590 mg, about 600 mg, about 610 mg, about 620 mg. hydrobromide is about 25 mg, about 30 mg, about 35 mg. about 630 mg, about 640 mg, about 650 mg, about 660 mg. about 670 mg, about 680 mg, about 690 mg, about 700 mg. about 40 mg, about 45 mg, about 50 mg, about 55 mg, about about 710 mg, about 720 mg, about 730 mg, about 740 mg. 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 about 750 mg, about 760 mg, about 770 mg, about 780 mg. mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg. about 790 mg, about 800 mg, about 810 mg, about 820 mg. about 105 mg, about 110 mg, about 115 mg, about 120 mg. about 830 mg, about 840 mg, about 850 mg, about 860 mg. about 125 mg, about 130 mg, about 135 mg, about 140 mg. about 870 mg, about 880 mg, about 890 mg, about 900 mg. about 145 mg, about 150 mg, about 155 mg, about 160 mg. about 910 mg, about 920 mg, about 930 mg, about 940 mg. about 165 mg, about 170 mg, about 175 mg, about 180 mg. about 950 mg, about 960 mg, about 970 mg, about 980 mg. about 185 mg, about 190 mg, about 195 mg. or about 200 about 990 mg. or about 1000 mg, or even greater. ng. 0188 In another embodiment described herein, the phar (0191 In one embodiment described herein, the active maceutical composition described herein, comprises an pharmaceutical ingredient comprises dextromethorphan active pharmaceutical ingredient of about 1000 mg, about hydrobromide and menthol, wherein the dose of dex 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg. tromethorphan hydrobromide is as described of, and the about 1250 mg, about 1300 mg, about 1350 mg, about 1400 dose of menthol is about 1 mg to about 10 mg, including all mg, about 1450 mg, about 1500 mg, about 1550 mg, about integers within the specified range. In one aspect, the dose 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg. of menthol is about 0.09 mg. In one aspect, the dose of about 1800 mg, about 1850 mg, about 1900 mg, about 1950 menthol is about 1 mg. In another aspect, the dose of mg, about 2000 mg, about 2050 mg, about 2100 mg, about menthol is about 2 mg. In another aspect, the dose of 2150 mg, about 2200 mg, about 2250 mg, about 2300 mg. menthol is about 3 mg. In another aspect, the dose of about 2350 mg, about 2400 mg, about 2450 mg, about 2500 menthol is about 3 mg. In another aspect, the dose of mg, about 2550 mg, about 2600 mg, about 2650 mg, about menthol is about 4 mg. In another aspect, the dose of 2700 mg, about 2750 mg, about 2800 mg, about 2850 mg. menthol is about 5 mg. In another aspect, the dose of about 2900 mg, about 2950 mg, about 3000 mg, about 3050 menthol is about 5 mg. In another aspect, the dose of mg, about 3100 mg, about 3150 mg, about 3200 mg, about menthol is about 6 mg. In another aspect, the dose of 3250 mg, about 3300 mg, about 3350 mg, about 3400 mg. menthol is about 7 mg. In another aspect, the dose of about 3450 mg, about 3500 mg, about 3550 mg, about 3600 menthol is about 8 mg. In another aspect, the dose of mg, about 3650 mg, about 3700 mg, about 3750 mg, about menthol is about 9 mg. In another aspect, the dose of 3800 mg, about 3850 mg, about 3900 mg, about 3950 mg. menthol is about 10 mg. about 4000 mg, about 4050 mg, about 4100 mg, about 4150 0.192 In one embodiment, the total dosage of dex mg, about 4200 mg, about 4250 mg, about 4300 mg, about tromethorphan hydrobromide and menthol administered in a 4350 mg, about 4400 mg, about 4450 mg, about 4500 mg. 24-hour period is about 20 mg to about 200 mg. In one about 4550 mg, about 4600 mg, about 4650 mg, about 4700 aspect, the total dosage of dextromethorphan hydrobromide mg, about 4750 mg, about 4800 mg, about 4850 mg, about and menthol administered in a 24-hour period is about 30 4900 mg, about 4950 mg, or about 5000 mg. or even greater. mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg. 0189 In another embodiment described herein, the dos about 80 mg, about 90 mg, about 100 mg, about 110 mg. age form can be administered, for example, 1x, 2x, 3x, 4x. about 120 mg, about 125 mg, about 130 mg, about 135 mg. 5.x, 6.x, 7.x, or 8x, per day. One or more dosage form can be about 140 mg, about 145 mg, about 150 mg, about 155 mg. US 2016/0279056A1 Sep. 29, 2016

about 160 mg, about 165 mg, about 170 mg, about 175 mg. menthol is administered 4 times daily for a total of 80 mg to about 180 mg, about 185 mg, about 190 mg, about 195 mg. reach a desired therapeutic efficacy. In another aspect, 20 mg or about 200 mg. of dextromethorphan and menthol is administered 6 times 0193 In one embodiment, the total dosage of dex daily for a total of 120 mg to reach a desired therapeutic tromethorphan hydrobromide and menthol administered in a efficacy. In another aspect, 20 mg of dextromethorphan and 24-hour period is about 20 mg to about 160 mg per 24-hour menthol is administered 8 times daily for a total of 160 mg period including all iterations of integers within the specified to reach a desired therapeutic efficacy. range. In another embodiment, the total dosage of dex 0.195. In one embodiment, the dosage can contain an tromethorphan hydrobromide and menthol administered in a amount of dextromethorphan hydrobromide effective for 24-hour period is about 20 mg to about 40 mg per 24-hour treatment, amelioration, prophylaxis, or reducing the onset period including all iterations of integers within the specified of or symptoms of mild, moderate, or severe cold and cough. range. In another embodiment, the total dosage of dex 0196. In another embodiment, the dosage can contain an tromethorphan hydrobromide and menthol administered in a amount of dextromethorphan hydrobromide and an amount 24-hour period is about 30 mg to about 50 mg per 24-hour of one or more nasal decongestants, antitussives, expecto period including all iterations of integers within the specified rants, or antihistamines, or a mixture or combination thereof range. In another embodiment, the total dosage of dex for the treatment, amelioration, prophylaxis, or reducing the tromethorphan hydrobromide and menthol administered in a onset of or symptoms of a cough or cold. 24-hour period is about 40 mg to about 60 mg per 24-hour 0.197 In one embodiment described herein, the active period including all iterations of integers within the specified pharmaceutical ingredient comprises thymol having a dose range. In another embodiment, the total dosage of dex of about 0.0005 mg to about 0.002 mg, including all integers tromethorphan hydrobromide and menthol administered in a within the specified range. In one aspect, the dose of thymol 24-hour period is about 50 mg to about 80 mg per 24-hour is about 0.0005 mg. In one aspect, the dose of thymol is period including all iterations of integers within the specified about 0.00075 mg. In another aspect, the dose of thymol is range. In another embodiment, the total dosage of dex about 0.001 mg. In another aspect, the dose of thymol is tromethorphan hydrobromide and menthol administered in a about 0.0015 mg. In another aspect, the dose of thymol is 24-hour period is about 60 mg to about 90 mg per 24-hour about 0.002 mg. In another aspect, the dose of thymol is period including all iterations of integers within the specified about 0.0005 mg, about 0.0006 mg, about 0.0007 mg, about range. In another embodiment, the total dosage of dex 0.0008 mg, about 0.0009 mg, about 0.001 mg, or about tromethorphan hydrobromide and menthol administered in a 0.002 mg. 24-hour period is about 70 mg to about 100 mg per 24-hour 0.198. In one embodiment described herein, the active period including all iterations of integers within the specified pharmaceutical ingredient comprises thymol and menthol, range. In another embodiment, the total dosage of dex wherein the dose of thymol is as described of, and the dose tromethorphan hydrobromide and menthol administered in a of menthol is about 1 mg to about 10 mg, including all 24-hour period is about 80 mg to about 110 mg per 24-hour integers within the specified range. In one aspect, the dose period including all iterations of integers within the specified of menthol is about 0.09 mg. In one aspect, the dose of range. In another embodiment, the total dosage of dex menthol is about 1 mg. In another aspect, the dose of tromethorphan hydrobromide and menthol administered in a menthol is about 2 mg. In another aspect, the dose of 24-hour period is about 90 mg to about 120 mg per 24-hour menthol is about 3 mg. In another aspect, the dose of period including all iterations of integers within the specified menthol is about 3 mg. In another aspect, the dose of range. In another embodiment, the total dosage of dex menthol is about 4 mg. In another aspect, the dose of tromethorphan hydrobromide and menthol administered in a menthol is about 5 mg. In another aspect, the dose of 24-hour period is about 100 mg to about 130 mg per 24-hour menthol is about 5 mg. In another aspect, the dose of period including all iterations of integers within the specified menthol is about 6 mg. In another aspect, the dose of range. In another embodiment, the total dosage of dex menthol is about 7 mg. In another aspect, the dose of tromethorphan hydrobromide and menthol administered in a menthol is about 8 mg. In another aspect, the dose of 24-hour period is about 110 mg to about 140 mg per 24-hour menthol is about 9 mg. In another aspect, the dose of period including all iterations of integers within the specified menthol is about 10 mg. range. In another embodiment, the total dosage of dex 0199. In one embodiment, the dosage can contain an tromethorphan hydrobromide and menthol administered in a amount of thymol effective for treatment, amelioration, 24-hour period is about 120 mg to about 150 mg per 24-hour prophylaxis, or reducing the onset of or symptoms of dry period including all iterations of integers within the specified mouth, halitosis, stained teeth, oral pain or loss of enamel. range. In another embodiment, the total dosage of dex 0200. In another embodiment, the dosage can contain an tromethorphan hydrobromide and menthol administered in a amount of thymol and an amount of one or more chloro 24-hour period is about 130 mg to about 160 mg per 24-hour hexidine, ethanol or a mixture or combination thereof for the period including all iterations of integers within the specified treatment, amelioration, prophylaxis, or reducing the onset range. of or symptoms of dry mouth, halitosis, stained teeth, oral 0194 In another embodiment, the total dosage of dex pain or loss of enamel. tromethorphan hydrobromide and menthol administered in a 0201 In one embodiment described herein, the active 24-hour period is about 20 mg to about 160 mg and is pharmaceutical ingredient comprises nicotine polacrilex effective for the treatment of cough or illness is administered having a dose of about 2 mg to about 80 mg, including all in equal daily doses. In one aspect, 20 mg of dextrometho integers within the specified range. In one aspect, the dose rphan hydrobromide and menthol is administered 2 times of nicotine polacrilex is about 10 mg to about 70 mg, about daily for a total of 40 mg to reach a desired therapeutic 20 mg to about 60 mg, or about 30 mg to about 50 mg. In efficacy. In another aspect, 20 mg of dextromethorphan and another aspect, the dose of nicotine polacrilex is about 2 mg, US 2016/0279056A1 Sep. 29, 2016 24 about 4 mg, about 6 mg, about 8 mg, about 10 mg, about 20 fatigue, or malaise comprising administering to a subject in mg, about 40 mg, about 60 mg, or about 80 mg. need thereofan oral pharmaceutical composition Suitable for 0202 In one embodiment, the dosage can contain an chewing, sucking, or buccal dissolution as described herein. amount of nicotine polacrilex effective for treatment, ame 0209 Another embodiment described herein is a compo lioration, prophylaxis, or reducing the onset of or symptoms sition for treating, retarding the progression of prophylaxis of urge to Smoke. of delaying the onset of ameliorating, reducing the Symp 0203. In another embodiment, the dosage can contain an toms of, or promoting health, including but not limited to of amount of nicotine polacrilex and an amount of one or more one or more of pain, inflammation, cough, cold, fever, flu, bupropion, Varenicline or a mixture or combination thereof inflammation of the gastrointestinal tract, neoplasia, hyper for the treatment, amelioration, prophylaxis, or reducing the thyroidism, hypercalcemia, hyperparathyroidism, parathy onset of symptoms of urge to Smoke. roid carcinoma, indigestion, heartburn, irritable bowels, 0204. In one embodiment described herein, the active constipation, diarrhea, insomnia, dry mouth, halitosis, pharmaceutical ingredient comprises bismuth Subsalicylate stained teeth, oral pain, loss of enamel, urge to Smoke, having a dose of about 44 mg to about 4,192 mg, including fatigue, or malaise comprising administering to a subject in all integers within the specified range. In one aspect, the need thereofan oral pharmaceutical composition Suitable for dose of bismuth subsalicylate is about 50 mg to about 4000 chewing, sucking, or buccal dissolution as described herein. mg, about 75 mg to about 3,500 mg, or about 100 mg to 0210. Another embodiment described herein is a method about 3,000 mg. In another aspect, the dose of bismuth for treating, retarding the progression of prophylaxis of subsalicylate is about 50 mg, about 100 mg, about 150 mg. delaying the onset of ameliorating, or reducing the Symp about 200 mg, about 250 mg, about 300 mg, about 350 mg. toms of cough, cold, or congestion comprising the admin about 400 mg, about 450 mg, about 500 mg, about 550 mg. istration of a therapeutically effective amount of dex about 600 mg, about 650 mg, about 700 mg, about 750 mg. tromethorphan hydrobromide comprising any one of the about 800 mg, about 850 mg, about 900 mg, about 950 mg. pharmaceutical compositions described herein to a subject about 1,000 mg, about 1,500 mg, about 2,000 mg, about with cough, wherein the administration is sufficient to 2,500 mg, about 3,000 mg about 3,500 mg. or about 4,000 achieve a reduction of cough, congestion or cold related ng. symptoms. 0205. In one embodiment, the dosage can contain an 0211. In one aspect, after administration of any one the amount of bismuth subsalicylate effective for treatment, pharmaceutical compositions described herein, the Subject amelioration, prophylaxis, or reducing the onset of inflam experiences the side effects described herein at a rate of less mation of the gastrointestinal tract, neoplasia, hyperthyroid than about 10%. In another aspect, the subject experiences ism, hypercalcemia, hyperparathyroidism, parathyroid car the side effects described herein at a rate of less than about cinoma, indigestion, heartburn, irritable bowels, 2%, about 5%, about 10%, about 15%, about 20%, about constipation, diarrhea. 25%, about 30%, about 35%, about 45%, about 50%, about 0206. In another embodiment, the dosage can contain an 60%, about 70%, about 80%, or about 90%. amount of bismuth Subsalicylate and an amount of one or 0212 Another embodiment described herein is a method more of cimetidine, ranitidine, famotidine, ondansetron, for manufacturing the oral pharmaceutical composition omeprazole, lansoprazole, rabeprazole, esomeprazole, pan comprising the steps of: (a) preparing a gel fill composition toprazole, calcium Supplements, calcium hydroxide, allumi comprising a first solution and a second solution wherein: (i) num hydroxide, magnesium hydroxide, or a mixture or the first solution comprises polyvinylpyrrolidone K30, combination thereof for the treatment, amelioration, prophy orange flavor, citric acid, Sucralose, acesulfame potassium, laxis, or reducing the onset of inflammation of the gastro lycasin and water, one or more excipients in one or more intestinal tract, neoplasia, hyperthyroidism, hypercalcemia, solvents and mixed at a temperature no greater than 55° C. hyperparathyroidism, parathyroid carcinoma, indigestion, until dissolved and clear; (ii) the second solution comprises heartburn, irritable bowels, constipation, diarrhea. polyethylene glycol 400, propylene glycol and lactic acid 0207. The concentration of the active pharmaceutical and mixed until dissolved and clear, where the composition ingredient in the pharmaceutical composition depends on the comprises one or more film forming polymers, one or more specific active pharmaceutical ingredient, the disease to be plasticizers, one or more Sweeteners, one or more excipients treated, the condition of the patient, the age, and gender of in one or more solvents; (iii) adding dextromethorphan the patient, etc. The active pharmaceutical ingredient may be hydrobromide and menthol to the second solution and a well-known active pharmaceutical ingredient and a person mixing the first Solution and heating to no greater than 55° having ordinary skill in the art will be able to find informa C. until dissolved; and (iv) combining the first solution with tion as to the dosage of each active drug Substance and, the second solution and purging with nitrogen; (b) preparing accordingly, will know how to determine the amount of each a gel mass composition comprising one or more film form active drug Substance in the pharmaceutical composition. ing polymers, one or more plasticizers, one or more Sweet 0208 Another embodiment described herein is a method eners, one or more excipients and one or more solvents; (c) for treating, retarding the progression of prophylaxis of casting the gel composition into films or ribbons using delaying the onset of ameliorating, reducing the symptoms heat-controlled drums or Surfaces; and (d) forming a soft of or promoting health, including but not limited to of one dosage form comprising a liquid matrix fill using rotary die or more of pain, inflammation, cough, cold, fever, flu, encapsulation technology. inflammation of the gastrointestinal tract, neoplasia, hyper 0213 Another embodiment described herein is a method thyroidism, hypercalcemia, hyperparathyroidism, parathy for manufacturing the oral pharmaceutical composition of roid carcinoma, indigestion, heartburn, irritable bowels, claims comprising the steps of: (a) preparing a gel fill constipation, diarrhea, insomnia, dry mouth, halitosis, composition comprising a first gel fill solution and a second stained teeth, oral pain, loss of enamel, urge to Smoke, gel fill solution, wherein (i) the first gel fill solution com US 2016/0279056A1 Sep. 29, 2016 prises one or more hydrophilic vehicle, sweetener, flavor, tamper evident packaging provides reasonable evidence to thymol, in one or more solvents and is mixed at a tempera consumers that tampering has occurred. The tamper evident ture between 30-50° C. until dissolved; (ii) the second gel fill packaging additionally contains appropriate labelling state Solution comprises one or more hydrophilic vehicles and ments describing the features and evidences of the tamper menthol and is mixed at a temperature between 30-50° C. evident packaging. In one aspect, the tamper evident pack until dissolved; and (iv) combining the first gel fill solution aging comprises: bottles, film wrappers, blister or strip and the second gel fill solution, adding flavor and mixing for packs, bubble packs, heat shrink bands or wrappers, foil, at least 25 minutes; (b) preparing a gel mass composition paper, or plastic pouches, container mouth inner seals, tape comprising one or more film forming polymers, one or more seals, breakable caps, sealed metal tubes or plastic heat plasticizers, one or more Sweeteners, one or more excipients sealed tubes, sealed cartons, aerosol containers, cans includ and one or more solvents; (c) casting the gel composition ing metal and composite materials, or any combination into films or ribbons using heat-controlled drums or Sur thereof. The packaging may also comprise a dessicant and faces; and (d) forming a soft dosage form comprising a packing filler material to prevent the contents from shifting liquid matrix fill using rotary die encapsulation technology. or rattling. The packaging may also contain appropriate 0214. Another embodiment described herein is a method instructions for prescribing, instructions for use, warnings, for manufacturing the oral pharmaceutical composition of or other appropriate information. In another aspect, the claims comprising the steps of: (a) preparing a gel fill packaging may contain at least one daily regimen for the oral composition comprising a first solution, a flavor Solution, pharmaceutical composition. and a sweetener solution wherein: (i) the first solution 0216. Another embodiment described herein is a kit for comprises one or more hydrophilic vehicles, thickening dispensing any of the oral pharmaceutical compositions agents, flavors, and excipients and is mixed at a temperature described herein comprising: (a) at least one oral pharma between 30-70° C. until dissolved; (ii) the flavor solution ceutical composition; (b) at least one moisture proof dis comprises one or more hydrophilic vehicle and flavor and is pensing receptacle comprising blister or strip packs, an mixed at a temperature between 30-70° C. until dissolved; aluminum blister, a transparent or opaque polymer blister (iii) the Sweetener Solution comprises one or more Sweetener with pouch, polypropylene tubes, colored blister materials, in one or more solvent and nicotine and mixing until tubes, bottles, and bottles optionally containing a child dissolved; and (iv) combining the first solution, flavor solu resistant feature, optionally comprising a desiccant. Such as tion and Sweetener Solution and mixing to homogenize; (b) a molecular sieve or silica gel; and optionally (c) at least one preparing a gel mass composition comprising one or more daily regimen for the oral pharmaceutical composition; and film forming polymers, one or more plasticizers, one or (d) an insert comprising instructions or prescribing infor more Sweeteners, one or more excipients and one or more mation for the oral pharmaceutical composition. In one Solvents; (c) casting the gel composition into films or aspect described herein, the kit is useful for treating pain, ribbons using heat-controlled drums or Surfaces; and (d) inflammation, cough, cold, sinusitis, throat or bronchial forming a soft dosage form comprising a liquid matrix fill irritation, fever, flu, inflammation of the gastrointestinal using rotary die encapsulation technology. Another embodi tract, neoplasia, hyperthyroidism, hypercalcemia, hyper ment described herein is a method for manufacturing an oral parathyroidism, parathyroid carcinoma, indigestion, heart pharmaceutical composition comprising the steps of: (a) burn, irritable bowels, constipation, diarrhea, insomnia, dry preparing a gel fill composition comprising a color solution, mouth, halitosis, stained teeth, oral pain, loss of enamel, a flavor Solution and a gel Solution wherein: (i) the color cessation of urge to Smoke, fatigue, or malaise according to Solution comprises one or more colors and excipient in one any of the methods described herein. or more solvents and mixed at a temperature between 30-50 0217. It will be apparent to one of ordinary skill in the C. until dissolved; (ii) the flavor solution comprises one or relevant art that Suitable modifications and adaptations to the more of plasticizer, menthol and flavor and mixed at a compositions, formulations, methods, processes, and appli temperature between 30-50° C. until dissolved; (iii) the gel cations described herein can be made without departing Solution comprises soaking one or more film forming poly from the scope of any embodiments or aspects thereof. The mer, plasticizer, Sweeteners in one or more solvents, then compositions and methods provided are exemplary and are heated at a temperature between 30-70° C. until dissolved; not intended to limit the scope of any of the specified (iv) combining the color Solution, flavor Solution, and gel embodiments. All of the various embodiments, aspects, and Solution and adding bismuth Subsalicylate and mixing at a options disclosed herein can be combined in any and all temperature of 20-60° C. until dissolved; (b) preparing a gel variations or iterations. The scope of the compositions, mass composition comprising one or more film forming formulations, methods, and processes described herein polymers, one or more plasticizers, one or more Sweeteners, include all actual or potential combinations of embodiments, one or more excipients and one or more solvents; (c) casting aspects, options, examples, and preferences herein the gel composition into films or ribbons using heat-con described. The exemplary compositions and formulations trolled drums or Surfaces; and (d) forming a soft dosage form described herein may omit any component, Substitute any comprising a liquid matrix fill using rotary die encapsulation component disclosed herein, or include any component technology. disclosed elsewhere herein. The ratios of the mass of any 0215. In another embodiment described herein, one or component of any of the compositions or formulations more of the oral pharmaceutical compositions described disclosed herein to the mass of any other component in the herein are contained and dispensed in a kit comprising a formulation or to the total mass of the other components in tamper evident packaging. The term “tamper evident’ or the formulation are hereby disclosed as if they were “tamper resistant” refers to a packaging of any kind that expressly disclosed. Should the meaning of any terms in any readily displays or permits an individual to observe any of the patents or publications incorporated by reference physical interference or manipulation of said packaging. The conflict with the meaning of the terms used in this disclo US 2016/0279056A1 Sep. 29, 2016 26

Sure, the meanings of the terms or phrases in this disclosure TABLE 5-continued are controlling. Furthermore, the foregoing discussion dis closes and describes merely exemplary embodiments. All Exemplary Liquisoft Composition patents and publications cited herein are incorporated by Capsule Shell Formulation reference herein for the specific teachings thereof. Component Formula 3 Formula 4 Formula 5 EXAMPLES Maltitol 18.1 18.1 Glycerol 18.9 18.9 32.3 Xylitol 4.8 Example 1 Mannitol 2.4 2.4 Sucralose O.2 O.2 O.2 0218 Exemplary capsule shell and matrix compositions Citric Acid O.S O.S O.S useful for producing Liquisoft capsules as described herein Glycine 4.8 are shown in Table 4. Composition components are set forth Flavors by weight percentage of the total weight of the composition. Water 25.8 25.8 32.5 Such compositions may be encapsulated using rotary die TOTAL 100% 100% 100% encapsulation as described herein. VISCOSITY 4544 CP 2747 cP 1627 CP 0219 Formulas 1 and 2 were the first shell formulations developed to achieve faster disintegration time and prevent crosslinking of the gelatin shell with matrix fill components. Example 3 TABLE 4 0222. A dissolution study was performed using soft gel capsules comprising the pharmaceutical compositions Exemplary Liquisoft Composition shown in Tables 4 and 5. The compositions of Formula 1 and Capsule Shell Formulation Formula 2 served as controls. The time for complete disso Component Formula 1 Formula 2 lution and average viscosity of each formula was recorded. Further compositions were formulated to achieve a higher Gelatin, 250 Bloom 24.3 Viscosity. Gelatin, 150 Bloom 29.2 Gelatin, 100 Bloom 4.9 Gelatin Hydrolysate TABLE 7 Hydrolyzed Collagen Powdered Cellulose 1.9 Exemplary Liquisoft Composition Maltitol 25.7 Glycerol 32.O 19.1 Complete Average Xylitol 4.8 Dissolution Viscosity Sucralose Formula (min) (cP) Citric Acid O.S Flavors O.S Formula 1 A mass of gel remains NT Water 32.3 2S.O after 20 minutes Formula 2 2O 3497 TOTAL 100% 100% Formula 3 19.5 4544 VISCOSITY 3497 CF Formula 4 18 2747 Formula 5 17.5 1627

Example 2 Example 4 0220 Exemplary capsule shell and matrix compositions useful for producing Liquisoft capsules as described herein 0223 Exemplary capsule shell and matrix compositions are shown in Table 5. Composition components are set forth useful for producing Liquisoft capsules as described herein by weight percentage of the total weight of the composition. are shown in Table 6. Composition components are set forth Such compositions may be encapsulated using rotary die by weight percentage of the total weight of the composition. encapsulation as described herein. Such compositions may be encapsulated using rotary die 0221 Formulas 3, 4 and 5 were developed to include encapsulation as described herein. citric acid, glycine and gelatin hydrolysate to inhibit cross 0224 Formula 6 had a higher viscosity due to a total of linking, 250 Bloom gelatin was substituted for 150 Bloom 39% gelatin. Application batches were made using Formula 6 and Formula 7 shell formulas as placebo and active fill gelatin, and maltitol was used as the bulk Sweetener. formulations. Capsules were evaluated but required further TABLE 5 optimization to improve chewability. Exemplary Liquisoft Composition TABLE 6 Capsule Shell Formulation Exemplary Liquisoft Composition Component Formula 3 Formula 4 Formula 5 Capsule Shell Formulation Gelatin, 250 Bloom Component Formula 6 Formula 7 Gelatin, 150 Bloom 29.0 29.0 24.5 Gelatin, 100 Bloom 4.9 Gelatin, 250 Bloom Gelatin Hydrolysate 4.8 Gelatin, 150 Bloom 27.3 31.5 Hydrolyzed Collagen Gelatin, 100 Bloom 7.9 Powdered Cellulose Gelatin Hydrolysate S.O US 2016/0279056A1 Sep. 29, 2016 27

TABLE 6-continued 0228. Formula 10 was revised to increase the amount of water to 20%, resulting in Formula 1 1. Formula 1 1 was Exemplary LiquiSoft Composition encapsulated, but was further revised to reduce the viscosity. Capsule Shell Formulation Hence, Formula 12 was developed whereby the amount of Component Formula 6 Formula 7 water was increased to 22% and the total amount of gelatin Hydrolyzed Collagen was limited to 31% resulting in a viscosity of approximately Powdered Cellulose 4300 cp. Formula 12 was used for GMP batch manufactur Maltitol 16.1 ing to evaluate the combination product. Glycerol 32.O 19.2 Xylitol 4.8 TABLE 8 Mannitol Sucralose O.2 O.2 Exemplary Liquisoft Composition Citric Acid O.S O.S Glycine S.O Capsule Shell Formulation Flavors Component Formula 11 Formula 12 Water 22.O 27.5 Gelatin, 250 Bloom TOTAL 100% 100% Gelatin, 150 Bloom 22.7 18.9 VISCOSITY 13,418 cP 5,748 cP Gelatin, 100 Bloom 9.7 8.1 Gelatin Hydrolysate S.O S.1 Hydrolyzed Collagen Powdered Cellulose Example 5 Maltitol 16.3 16.3 Glycerol 19.7 23.3 Xylitol S.O 2.5 0225 Exemplary capsule shell and matrix compositions Mannitol useful for producing Liquisoft capsules as described herein Sucralose O.2 O.2 are shown in Table 7. Composition components are set forth Citric Acid O.S O.S by weight percentage of the total weight of the composition. Glycine Such compositions may be encapsulated using rotary die Flavors O.S O.S encapsulation as described herein. Water 2O2 24.8 0226. The composition of Formulas 8,9, and 10 included TOTAL 100% 100% increased amounts of 100 Bloom gelatin to minimize shell VISCOSITY 13,226 cP 4,341 cP toughness. As seen in Table 7, increased amounts of 100 Bloom gelatin resulted in decreased viscosity but encapsu lation was unsuccessful. Formula 10 was revised further. Example 7 TABLE 7 0229. Exemplary capsule shell and matrix compositions useful for producing Liquisoft capsules as described herein Exemplary Liquisoft Composition are shown in Table 9. Composition components are set forth Capsule Shell Formulation by weight percentage of the total weight of the composition. Component Formula 8 Formula 9 Formula 10 Such compositions may be encapsulated using rotary die Gelatin, 250 Bloom encapsulation as described herein. Gelatin, 150 Bloom 14.2 18.7 19.8 Gelatin, 100 Bloom 14.2 12.5 13.1 0230. Formula 13 was used for GMP batch manufacture. Gelatin Hydrolysate 4.9 4.9 5.2 Hydrolyzed Collagen TABLE 9 Powdered Cellulose Maltitol 15.7 16.7 18.8 Exemplary Liquisoft Composition Glycerol 18.9 2O2 20.6 Capsule Shell Formulation Xylitol O.S O.S 5.2 Mannitol Component Formula 13 Sucralose O.S O.S O.2 Citric Acid O.S O.2 O.S Gelatin, 250 Bloom Glycine Gelatin, 150 Bloom 19.3 Flavors Gelatin, 100 Bloom 8.3 Water 30.6 25.8 16.6 Gelatin Hydrolysate Hydrolyzed Collagen 4.9 TOTAL 100% 100% 100% Powdered Cellulose VISCOSITY 2,628 cP 1,899 cP 8,376 cP Maltitol 16.8 Glycerol 24.0 Xylitol 2.6 Mannitol Sucralose O.2 Example 6 Citric Acid O.S Glycine 0227 Exemplary capsule shell and matrix compositions Flavors O.S useful for producing Liquisoft capsules as described herein Water 22.7 are shown in Table 8. Composition components are set forth TOTAL 100% by weight percentage of the total weight of the composition. VISCOSITY Such compositions may be encapsulated using rotary die encapsulation as described herein. US 2016/0279056A1 Sep. 29, 2016 28

Example 8 TABLE 11-continued 0231 Exemplary capsule shell and matrix compositions useful for producing Liquisoft capsules as described herein Exemplary Liquisoft Composition are shown in Table 10. Composition components are set Matrix Formulation forth by weight percentage of the total weight of the com Component Formula 17 Formula 18 Formula 19 position. Such compositions may be encapsulated using Polyvinylpyrrollidone K30 1.6 1.6 1.6 rotary die encapsulation as described herein. Maltitol 52.5 52.5 52.5 0232 Formulas 14, 15, and 16 were the initial matrix Sucralose O.6 O6 O.6 prototypes for dextromethorphan hydrobromide (30 mg) and Citric Acid 1.6 1.6 1.O menthol (5 mg). Three different taste-masking agents were Lactic Acid 1.6 1.6 1.O Sodium Citrate 1.6 1.6 1.O tested: mannitol, thaumatin (Talin R) and glycyrrhizic acid Mannitol salts (MagnaSweet(R). Thaumatin resulted in the most effec Thaumatin (Talin (R) O.S O.3 tive taste masking of the dextromethorphan hydrobromide, Glycyrrhizic acid salts O6 O.2 but resulted in a hazy appearance. (MagnaSweet (R) Water 3.5 3.4 5.2 Dextromethorphan 1.O 1.O 1.O TABLE 10 Hydrobromide Exemplary Liquisoft Composition Menthol O.S O.S O.S Matrix Formulation TOTAL 100% 100% 100% Component Formula 14 Formula 15 Formula 16 Propylene Glycol 8.1 8.1 8.1 Polyethylene Glycol 400 25.4 25.4 25.4 Example 10 Polyvinylpyrrollidone K30 1.5 1.5 1.5 Maltitol SO.O SO.O SO.O 0236. Formula 19 was used for excipient compatibility Sucralose O.6 O6 O6 Citric Acid 1.O 1.O 1.O studies at stressed conditions (60° C. for 2 weeks) and the Lactic Acid 1.O 1.O 1.O results are recorded in Table 12. A 3% loss occurred in the Sodium Citrate 1.O 1.O 1.O sample taken on the day of fill compounding and a 3% Mannitol 3.0 menthol loss occurred by the time the fill was encapsulated. Thaumatin (Talin (R) 3.0 Glycyrrhizic acid salts 3.0 (MagnaSweet (R) TABLE 12 Water S.O S.O S.O Dextromethorphan 3.0 3.0 3.0 Exemplary Liquisoft Composition Hydrobromide Menthol O.S O.S O.S Formula 19 ASSay

TOTAL 100% 100% 100% (Talin-based Dextromethorphan fill) HBr Menthol Degradation Products To 99.9% 97.4% Dextromethorphan: 0.01% Example 9 1 week at 100.0% 95.0% Dextromethorphan: 0.01% 60° C. RRT 0.95: 0.03% 0233 Exemplary capsule shell and matrix compositions 2 weeks at 99.7% 93.5% Dextromethorphan: 0.01% useful for producing Liquisoft capsules as described herein 60° C. RRT 0.95: 0.03% are shown in Table 11. Composition components are set forth by weight percentage of the total weight of the com position. Such compositions may be encapsulated using rotary die encapsulation as described herein. Example 11 0234 Formulas 17, 18 and 19 were formulated with a reduced amount of dextromethorphan hydrobromide (10 0237 Exemplary capsule shell and matrix compositions mg) and menthol (5 mg). useful for producing Liquisoft capsules as described herein 0235. Thaumatin and glycyrrhizic acid salts were are shown in Table 11. Composition components are set employed with the lower active pharmaceutical ingredient forth by weight percentage of the total weight of the com dose, individually and as a combination. Thaumatin was position. Such compositions were encapsulated using rotary found to be the most effective at taste masking at the 10 mg die encapsulation as described herein. dose and showed no precipitation (Formula 17). Thus, the 0238 Formulas 20 and 21 were used as batch formula glycyrrhizic acid salts were not further assessed for chemical tions for active lots. Formula 20 is the formulation for the stability. Thus, Formula 19 was formulated using thaumatin amount per capsule. Formula 21 is the formulation for the and used for excipient compatibility studies. amount per batch.

TABLE 11 TABLE 13 Exemplary Liquisoft Composition Exemplary Liquisoft Composition Matrix Formulation Matrix Formulation

Component Formula 17 Formula 18 Formula 19 Component Formula 20 Formula 21 Propylene Glycol 8.4 8.4 8.4 Propylene Glycol 8.4 8.4 Polyethylene Glycol 400 26.6 26.6 26.6 Polyethylene Glycol 400 25.6 26.6 US 2016/0279056A1 Sep. 29, 2016 29

TABLE 13-continued TABLE 15-continued Exemplary LiquiSoft Composition Exemplary Liquisoft Composition Matrix Formulation Matrix Formulation

Component Formula 20 Formula 21 Results at T = 1 months Results at Initial T = 0 40° C.;75% RH Polyvinylpyrrollidone K30 1.6 1.6 Maltitol 52.7 52.7 Degradation Products Results Sucralose O.6 O6 Citric Acid 1.O 1.O Dextromethorphan Hbr RRT 1.09: 0.05% RRT 1.09: 0.05% Lactic Acid 1.O 1.O Total: 0.05% Total 0.05% Sodium Citrate Menthol None Detected RRT 1.15: 0.1%; Mannitol RRT 1.73: 0.2%, Thaumatin (Talin (R) O.S O.S Total 0.03% Glycyrrhizic acid salts (MagnaSweet (R) Dissolution Study Results Water 7.1 7.1 Dextromethorphan 1.O 1.O Dextromethorphan HBr Dextromethorphan HBr Hydrobromide Menthol O.S O.S 15 minutes: 99% 15 minutes: 99% 30 minutes: 98% 30 minutes: 98% TOTAL 100% 100% 45 minutes: 98% 45 minutes: 98% 60 minutes: 98% 60 minutes: 98%

Example 12 Example 14 0239 Formula 21 was encapsulated and gel parameters were determined. Encapsulation was performed using a 6.2 0241 Exemplary capsule shell and matrix compositions inch die with cavity of a 1 g square chewel capsule with useful for producing Liquisoft capsules as described herein target fill weight of 960 mg. The medicine was fed into the are shown in Table 16. Composition components are set encapsulation machine using gravity feed from the 60 L forth by weight percentage of the total weight of the com tank. Medium chain triglycerides (MCT) were utilized as position. Such compositions were encapsulated using rotary lubricant during encapsulation. The product was encapsu die encapsulation as described herein. lated at ambient temperatures and dried using a tumble drier. Gel parameters were recorded in Table 14. TABLE 16

TABLE 1.4 Exemplary Liquisoft Composition Weight Exemplary Liquisoft Composition Percentage Encapsulation Parameters Formula 21 Component (%) Matrix Formulation Capsule Shell Formulation Gel Age (hrs) 4-72 Machine Die Speed (rpm) 3.0 Gelatin, 150 Bloom 19.3 Gelatin, 100 Bloom 8.3 Die pressure (psi) 75 Hydrolyzed Collagen 4.9 Target Ribbon Thickness 0.028 inches (Range Glycerol 24.0 0.025-0.031 inches) Maltitol 16.8 Fill weight (mg) Target: 960 mg Xylitol 2.6 Alert Limits: 941-979 mg Sucralose O.2 Control Limits: 912-1008 mg Citric Acid O.S Water 23.0

TOTAL 100% Example 13 Matrix Fill Formulation 0240 Batch analytical data for Formula 21 was deter Propylene Glycol 8.4 mined and recorded in Table 15. Results were recorded at Polyethylene Glycol 400 26.6 Polyvinylpyrrollidone K30 1.6 time, T=0 and again at time, T=1 month at a temperature of Citric Acid 1.O 40° C. and 75% relative humidity (RH). Lactic Acid 1.O Sodium Citrate TABLE 1.5 Maltitol 52.7 Sucralose O.6 Exemplary Liquisoft Composition Mannitol Matrix Formulation Thaumatin (Talin (R) O.S Glycyrrhizic acid salts Results at T = 1 months (MagnaSweet (R) Results at Initial T = 0 40° C.;75% RH Water 5.5 Dextromethorphan Hydrobromide 1.O Assay Results Menthol O.S Dextromethorphan Hbr 98.0% label claim 100.4% label claim TOTAL 100% Menthol 97.0% label claim 100.4% label claim US 2016/0279056A1 Sep. 29, 2016 30

Example 15 0242 Exemplary capsule shell and matrix compositions useful for producing Liquisoft capsules as described herein are shown in Table 17. Composition components are set forth by weight percentage of the total weight of the com position. Such compositions may be encapsulated using rotary die encapsulation as described herein. TABLE 17 Exemplary Liquisoft Compositions Weight Percentage (%

Component EX 1 EX 2 EX 3 EX 4 EX 5 EX 6 Capsule Shell Formulation Polymers 27 32 35 39 40 55 Plasticizers 61.5 49.5 43.8 34.5 29.5 29.9 Polymer Modifiers 1 O.1 0.7 0.7 1. 1.3 Solvent 9.4 17.4 20.4 25.4 28.4 13.4 Sweetener O.S O.S O.2 O.S O.S O.1 Flavor O.S O.S O.S O.S O.S O.S Coloring O.1 O.1 O.1 O.1 O.1 O.1

TOTAL 1OO 100 1OO 100 1OO 1OO Components and Relational Ratios

Ratio Gelatin to Plasticizer 0.44 O.64 O.80 1.11 1.33 1.83 Ratio Gelatin to Polymer Modifier 27.0 32O.O SO.O 55.7 40.0 423 Matrix Fill Formulation

Hydrophilic Vehicle 21 27 31 38 47 55 Sweeteners 68.5 61.5 55 52.75 34 31.5 Flavorings 1 4.1 2.5 3.24 5 5.5 Solvents 3.9 2.9 9.9 2.65 12.9 6.9 Coloring O.1 O.1 O.1 O.1 O.1 O.1 Active Pharmaceutical Ingredient 5.5 4.2 2.1 3.75 1. 1 (API) TOTAL 100% 100% 100% 100% 100% 100% Components and Relational Ratios Ratio API to remaining ingredients O.O6 O.04 O.O2 O.04 O.O1 O.O1 Ratio API to Hydrophilic Vehicle O.26 O16 O.O7 O.1 O.O2 O.O2

Example 16 TABLE 18-continued 0243 Exemplary capsule shell and matrix compositions Exemplary Liquisoft Compositions useful for producing Liquisoft capsules as described herein are shown in Table 18. Composition components are set Weight Percentage (% forth by weight percentage of the total weight of the com- Component EX 1 EX 2 EX3 EX4 EXS EX 6 position. Such compositions may be encapsulated using rotary die encapsulation as described herein. Lactate — — — 0.7 1 Sucralose O.S O.S O.2 O.S O.S O.1 Solvent 9.4 17.4 20.4 25.4 28.4 13.4 TABLE 1.8 Flavor O.S. O.S. O.S. O.S. O.S O.S Coloring O.1 O.1 O.1 O.1 O.1 O.1 Exemplary Liquisoft Compositions o TOTAL 100% 100% 100% 100% 100% 100% - Weight Percentage Co- Matrix Fill Formulation

Component EX 1 EX 2 EX3 EX4 EXIS EX 6 Propylene Glycol 2.5 5 6.5 7 9 6 Polyethylene Glycol 400 18 21 24 30 37 48 Capsule Shell Formulation Polyvinylpyrrollidone K30 0.5 1 OS 1 O.S 1 Gelatin 15OB 14 18 2O 22 27 31 Citric Acid O.33 1.37 0.83 1.08 1.67 2.75 Gelatin 100B 8 10 9 12 8 19 Lactic Acid O.33 1.37 0.83 1.08 1.67 2.75 Gelatin Hydrolysate 5 4 6 5 5 5 Sodium Citrate O.33 1.37 0.83 1.08 1.67 Glycerol 47 24 29 31 24.5 13.4 Maltitol 67 58 S1.5 48.S 29.5 28.75 Maltitol 19 10 14.5 Sucralose 1 1 O.S O.S 1.5 1.25 Xylitol 14.5 6.5 4.8 3.5 5 2 Mannitol O.S 3 Citrate 1 O.1 0.7 — 1.3 Talin 2.5 3.75 1.5 US 2016/0279056A1 Sep. 29, 2016 31

TABLE 18-continued TABLE 21 Exemplary Liquisoft Compositions Exemplary Liquisoft Fill Composition Weight Percentage (% Weight Quantity Percentage Component EX 1 EX 2 EX3 EX4 EXS EX 6 Component (mg) (%) MagnaSweet (R) 3 Dextromethorphan HBr, USP 15.8% 1.6 Solvent 3.9 2.9 9.9 2.65 12.9 6.9 L-Menthol Crystals, USP 2.5 O.3 Coloring O.1 O.1 O1 O.1 O.1 O.1 PEG 400, USP 195.0 19.5 Active Pharmaceutical 5.5 4.2 2.1 3.75 1 1 Propylene Glycol, USP 80.0 8.0 Ingredient (API) Polyvinylpyrrollidone K30 12.O 1.2 Lactic Acid, USP 1O.O 1.O TOTAL 100% 100% 100% 100% 100% 100% Citric Acid 1O.O 1.O Y-Cyclodextrin 22.O 2.2 Sucralose, USP 5.9 O6 Acesulfame potassium 6.O O6 Lycasin 80/55 S49.8 55 Example 17 Orange Flavor PB72 16 16 Purified Water 75 7.5 0244 Exemplary capsule shell and matrix compositions useful for producing Liquisoft capsules as described herein TOTAL 1OOO.O 100.0% are shown in Tables 19-21. Composition components are set *Dextromethorphan H Br is corrected for its impurity (impurity factor of 0.951). forth by the quantity and weight percentage of the total weight of the composition. Example 18 TABLE 19 0245 Exemplary capsule shell and matrix compositions Exemplary LiquiSoft Shell Composition useful for producing Liquisoft capsules as described herein Weight are shown in Tables 22-23. Composition components are set Quantity Percentage forth by weight percentage of the total weight of the com Component (kg) (%) position. Such compositions may be encapsulated using Gelatin, 150 Bloom Limed Bone, NF 79.5 19.3 rotary die encapsulation as described herein. Gelatin, 100 Bloom Limed Bone, NF 34.2 8.30 Hydrolyzed Collagen Peptan B 5000 HD 2O.O 4.85 TABLE 22 Glycerin, USP 98.7 23.95 Citric Acid Anhydrous, USP 2.16 O.S2 Exemplary Liquisoft Shell Composition Lycasin 80/55 69.0 16.75 Xylisorb 300, USP 10.8 2.62 Weight Mass per Orange Flavor PB72 2.16 O.S2 Quantity Percentage capsule FD&C Yellow #6, Granular O.08 O.O2 Component (kg) (%) (mg) FD&C Red #40 O.O2 O.0049 Sucralose, USP O.84 O.2O Gelatin, 150 Bloom Limed 79.50 19.9 111.2 Purified Water 94.6 22.96 Bone Gelatin, 100 Bloom Limed 34.20 8.6 47.8 TOTAL 412O6 100.0% Bone Hydrolyzed Collagen 2O.OO S.O 28.0 Peptan B 5000 HD Lycasin 80/55 67.60 16.9 94.6 TABLE 20 Glycerin, USP 98.70 24.7 138.0 Purified Water (I)* 82.OO 2O.S 114.7 Exemplary Liquisoft Fill Composition FD&C Yellow #6, Granular O.O8 O O.1 FD&C Red #40 O.O2 O O.O Weight Purified Water (II)** 1.OO O.3 1.4 Quantity Percentage Orange Flavor PB72 3.SO O.9 4.9 Component (mg) (%) Xylisorb 300, USP 1O.OO 2.5 15.1 Citric Acid Anhydrous, 2.10 O.S 3.0 Dextromethorphan HBr, USP 15.8% 1.6 USP L-Menthol Crystals, USP O.9 O.1 Sucralose, USP O.84 O.2 1.2 PEG 400, USP 1950 19.5 Propylene Glycol, USP 80.0 8.0 TOTAL 399.54 100.0% S600 Polyvinylpyrrollidone K30 12.O 1.2 Lactic Acid, USP 1O.O 1.O Citric Acid 1O.O 1.O Y-Cyclodextrin 22.O 2.2 TABLE 23 Sucralose, USP 5.9 O.6 Acesulfame potassium 6.O O.6 Exemplary Liquisoft Fill Compositions Lycasin 80/55 SS1.4 55.1 Orange Flavor PB72 16.O 1.6 Weight Weight Purified Water 75.0 7.5 Quantity Percentage Quantity Percentage Component (mg) (%) (mg) (%) TOTAL 1OOO.O 100.0% Dextromethorphan 1O.S2 1.1 1O.S2 1.1 *Dextromethorphan HBr is corrected for its impurity (impurity factor of 0.951). HBR US 2016/0279056A1 Sep. 29, 2016 32

TABLE 23-continued TABLE 25-continued Exemplary Liquisoft Fill Compositions Exemplary Liquisoft Fill Composition Weight Weight Quantity Percentage Quantity Percentage Weight Component (mg) (%) (mg) (%) Quantity Percentage L-Menthol O.65 O.1 2.50 O.3 Component (kg) (%) PEG 400 21O.OO 21.0 21O.OO 21.O Propylene Glycol 8O.OO 8.0 8O.OO 8.O Lactic Acid 1O.OO 1.O 1O.OO 1.O Glycerin, USP 12.45 41.5 Purified Water 55.00 5.5 55.00 5.5 Propylene Glycol, USP O.60 2.0 Citric Acid 1O.OO 1.O 1O.OO 1.O Polysorbate 20, NF O.60 2.0 Polyvinyl- 12.00 1.2 12.00 1.2 pyrrollidone K30 Purified Water 3.0 1O.O Sucralose S.90 O6 S.90 O.6 Citric Acid 0.075 O.3 Acesulfame 6.OO O6 6.OO O.6 Polyvinylpyrrollidone K30 O.90 3.0 potassium Sucralose, USP O.15 O.S Lycasin 80/55 579.93 58.0 S78.08 57.8 Orange Flavor 2O.OO 2.0 2O.OO 2.0 Thymol, Crystal NF O.OO12 O Eucalyptol O.O276 O. TOTAL 1OOO.O 100.0% 1OOO.O 100.0% Peppermint Oil O.O90 O.3 Methyl salicylate O.018 O.1

Example 19 TOTAL 29.9988 100.0% 0246 Exemplary capsule shell and matrix compositions useful for producing Liquisoft capsules as described herein are shown in Tables 24-25. Composition components are set Example 20 forth by weight percentage of the total weight of the com position. Such compositions may be encapsulated using 0247 Exemplary capsule shell and matrix compositions rotary die encapsulation as described herein. useful for producing Liquisoft capsules as described herein are shown in Tables 26-27. Composition components are set TABLE 24 forth by weight percentage of the total weight of the com position. Such compositions may be encapsulated using Exemplary Liquisoft Shell Composition rotary die encapsulation as described herein. Weight Quantity Percentage TABLE 26 Component (kg) (%) Gelatin, LB, 100 Bloom 114.O 27.76 Exemplary Liquisoft Shell Composition Hydrolyzed Collagen Peptan B 5000 HD 2O.O 4.87 Lycasin 80/55 69.0 16.80 Glycerin, USP 88.0 21.43 Weight Propylene Glycol, USP 4.0 0.97 Component Quantity (kg) Percentage (%) Purified Water (I) 89.0 21.67 FD&C Yellow #6, Granular O.O2616 O.O1 Gelatin, LB, 150 Bloom 22 22.00 FD&C Blue #1 O.O1132 O.OO3 Gelatin, LB, 100 Bloom 10 10.00 Purified Water (II) 1.O O.24 Maltitol Syrup 17.25 17.25 Peppermint Oil O.396 O.10 Glycerin 99.7% 19.7 19.70 Xylisorb 300, USP 10.2 2.48 Citric Acid Anhydrous, USP 2.16 O.S3 Titanium dioxide 2.1 2.10 Sucralose, USP O.84 O.20 Purified Water I 18.2 18.20 Purified Water (III) 12.0 2.92 Gelatin Hydrolysate 5 5.00 TOTAL 410.63 100.0%

TABLE 25 Pepperment Oil O.3 O.30 TOTAL * 101 101.0 Exemplary Liquisoft Fill Composition Weight Quantity Percentage Components in the shaded rows are mixed separately and then combined with the Component (kg) (%) mixture of the other components, Sorbitol Special 12.03 40.1 Shell contains 1% excess water to compensate vapor loss during vacuum deaeration, L-Menthol Flakes Pharma 0.057 O.2 US 2016/0279056A1 Sep. 29, 2016 33

TABLE 27 TABLE 29 Exemplary Liquisoft Fill Composition Exemplary Liquisoft Fill Composition Weight Weight Component Quantity (kg) Percentage (%) Component Quantity (kg) Percentage (%) Gelatin 70 Bloom LB 75.0 7.5 Glycerin O.630 1.78 Glycerin 1850 18.5 Gelatin hydrolysate O.630 1.78 Purified water I 107.0 10.7 Gelatin, 70B LB O.630 1.78 Gelatin hydrolysate 90.0 9.0 Sorbitol Special 9.450 26.72 Maltitol Syrup 370.0 37.0 Xylisorb 300 0.950 2.69 Glycine 50.0 5.0 Propylene glycol 1 2.050 5.80 Purified water II 30.0 3.0 PEG-400 O.32O O.90 Xylisorb 300 3O.O 3.0 Sucralose O.063 O.18 Purified Water 1* 3.670 10.38

Sucralose Purified water III 30.2 3.0 Menthol (crystal) O.O16 0.04 Nicotine Polacrilex (~20%)* 2O.O 2.0 Peppermint oil O.O16 0.04 TOTAL 1OOO.O 100.0% Propylene glycol 2 O.32O O.90 Simethicone O Components in the shaded rows are mixed separately and then combined with the mixture

of the other components, *The amount of active is variable according to the certificate of analysis (COA) of the TOTAL 35.37 100.0% Nicotine Polacrilex lot. The difference is accounted for by the adjusting the glycine amount, There is 1% extra water to compensate for vapor loss during vacuum deaeration, **Theoretical total batch weight is 35.02 kg after excluding 0.35 kg additional water. Nitrogen blanketing is maintained throughout the compounding process and storage Example 21 period, Components in the shaded rows are mixed separately and then combined with the mixture 0248 Exemplary capsule shell and matrix compositions of useful for producing Liquisoft capsules as described herein the other components. are shown in Tables 28-29. Composition components are set 1. An oral pharmaceutical composition Suitable for chew forth by weight percentage of the total weight of the com ing, sucking, or buccal dissolution comprising a shell encap position. Such compositions may be encapsulated using Sulating a matrix, rotary die encapsulation as described herein. the shell comprising: (a) one or more film-forming polymers; TABLE 28 (b) one or more plasticizers; Exemplary Liquisoft Shell Composition (c) one or more polymer modifiers; (d) one or more first Sweeteners; and Weight (e) one or more first solvents; and Component Quantity (kg) Percentage (%) a matrix comprising: Gel Component Mass (kg) % weight (g) one or more hydrophilic vehicles; Gelatin, LB, 100 Bloom 52.64 12.82 (h) one or more flavors; Gelatin, LB, 150 Bloom 77.20 18.79 (i) one or more second Sweeteners; Glycerin 91.84 22.36 () one or more second solvents; and TiO2 Mass 6.OO 1.46 (k) one or more active pharmaceutical ingredients. Gelatin hydrolysate 9.72 2.37 2. The composition of claim 1, wherein the film-forming Maltitol syrup 57.48 13.99 polymer comprises one or more of gelatin, partially hydro Purified Water I 86.60 21.08 lyzed gelatin, hydrolyzed gelatin, hydrolyzed collagen, or combinations thereof. 3. The composition of claim 1, wherein the plasticizer comprises one or more of glycerol, maltitol, mannitol, Cherry Flavor 2.00 O.49 Xylitol, lycasin, or combinations thereof. 4. The composition of claim 1, wherein the polymer modifier comprises one or more of citric acid, acetic acid, lactic acid, malic acid, tartaric acid, or combinations thereof. 5. The composition of claim 1, wherein the hydrophilic TOTAL **** 410.76 100.0% vehicle comprises propylene glycol, polyethylene glycol Purified Water II serves to dissolve colorants. 400, polyvinylpyrrolidone K30, glycerin, sorbitol, xylitol, ** Cherry Flavor is added to the gel on the day of encapsulation. maltitol, or combinations thereof. Purified Water III serves to dissolve sweeteners. The sweetener solution is to be added to the gel on the day of encapsulation, 6. The composition of claim 1, wherein the first Sweetener **** There is 2% extra water to compensate for vapor loss during vacuum deaeration. comprises Sucralose, aspartame, Stevia, acesulfame potas Components in the shaded rows are mixed separately and then combined with the sium, Xylitol, or combinations thereof. mixture of the other components, 7. The composition of claim 1, wherein the flavoring comprises citric acid, lactic acid, sodium citrate, orange US 2016/0279056A1 Sep. 29, 2016 34 flavor, eucalyptol, peppermint oil, methyl salicylate, gly Sone, prednicarbate, prednisone, prednisolone, pred cine, or combinations thereof. nylidene, rimexolone, tiXocortol, triamcinolone, ulobetasol, 8. The composition of claim 1, wherein the second 5-fluorouracil, 5-fluorodeoxyuridine, capecitabine, calcium Sweetener comprises mannitol, maltitol. Xylitol, thaumatin, Supplements, calcimimetics, cinacalcet, nicotine, nicotine glycyrrhizic acid salts, acesulfame potassium, acesulfame polacrilex, bupropion, Varenicline, disulfiram, calcium car salts, sucralose, aspartame, Stevia, or combinations thereof. bimide, acamprosate, naltrexone, buprenorphine, metha 9. The composition of claim 1, wherein the active phar done, levacetylmethadol, lofexidine, betahistine, cinnariz maceutical ingredient comprises one or more of astemizole, ine, flunarizine, acetylleucine, gangliosides, ganglioside aZelastine, azatadine, brompheniramine, carbinoxamine, derivatives, tirilazad, riluzole, xaliproden, hydroxybutyric cetirizine, chlorpheniramine, clemastine, cyproheptadine, acid, amifampiridine, doxylamine, diphenhydramine hydro desloratadine, dexbrompheniramine, dexchlorpheniramine, chloride, melatonin, 1-theanine, monofluorophosphate, lac diphenhydramine, fexofenadine, hydroxy Zine, levocetiriz toferrin, lysozyme, lactoperoxidase, glucose oxidase, muta ine, loratadine, phenindamine, pheniramine, phenyltoloX nase, dextranase, glycerol, carbamide peroxide, sodium amine, promethazine, pyrilamine, terfenadine, bicarbonate, hydrated silica, silicon dioxide, polyvinylpyr tripelennamine, triprolidine, acetyl dihydrocodeine, benpro rolidone, potassium nitrate, Sodium monofluorophosphate, perine, benzonatate, benzylmorphine, bibenzonium bro Sodium tripolyphosphate, strontium chloride, potassium mide, butamirate, butorphanol, carbetapentane, chlophedia nitrate, strontium acetate, strontium chloride, calcium nol, clobutinol, clo?edanol, cloperastine, codeine, Sodium phosphosilicate, benzocaine, lidocaine, clove oil, dextromethorphan, dextromethorphan hydrobromide, Sodium bicarbonate, citric acid, tartaric acid, aspirin, ibu diacetylmorphine, dibunate, dihydrocodeine, dimenorfan, profen, aceclofenac, acemetacin, aloxiprin, azapropaZone, dimethoxanate, diphenhydramine, dropropizine, droxy benorilate, bromfenac, carprofen, celecoxib, choline mag propine, ethylmorphine, fedrilate, glaucine, hydrocodone, nesium salicylate, diclofenac, diflunisal, etodolac, etori hydromorphone, isoaminile, laudanum, levodropropizine, coxib, faislamine, fenbufen, fenoprofen, flurbiprofen, indo levomethadone, levopropoxyphene, meprotixol, methadone, metacin, ketoprofen, ketorolac, lornoxicam, loxoprofen, morclofone, nepinalone, nicocodine, nicodicodine, meloxicam, meclofenamic acid, mefenamic acid, meloxi normethadone, noscapine, oxeladin, oxolamine, pentoxyver cam, metamizole, methyl salicylate, magnesium salicylate, ine, pholcodine, pipaZetate, piperidione, prenoxdiazine, nabumetone, naproxen, nimeSulide, paracetamol, oxyphen tipepidine, Zipeprol, acetylcysteine, althea root, ambroXol. butaZone, parecoxib, phenylbutaZone, piroxicam, salicyl antimony pentasulfide, bromhexine, carbocisteine, cineole, salicylate, sulindac, sulfinpyrazone, suprofen, tenoxicam, combinations, combinations, creosote, dembrexine hydro tiaprofenic acid, tolmetin, Valdecoxib, acetylsalicylic acid, chloride, domiodol, dornase alfa, eprazinone, erdosteine, aloxiprin, aminophenaZone, anilides, benorilate, benzomor guaiacolsulfonate, guaifenesin, hederae helicis folium, phan derivatives, bezitramide, bucetin, buprenorphine, ipecacuanha, letosteine, levo Verbenone, mannitol, mesna, butorphanol, carbasalate calcium, choline Salicylate, neltenexine, potassium iodide, Senega, Sobrerol, Stepronin, codeine, dextromoramide, dextropropoxyphene, dezocine, tiopronin, tyloxapol, pseudoephedrine, cetirizine, loratadine, diamorphine, diflunisal, dihydrocodeine, dihydrocodone, fexofenadine, diphenhydramine, levocetirizine, deslorata dihydromorphine, diphenylpropylamine derivatives, dipyro dine, phenol, ethanol, thymol, eucalyptol, ethanol, methyl cetyl, ethenZamide, fentanyl, floctafenine, flupirtine, glafe salicylate, chlorhexidine gluconate, cetylpyridinium chlo nine, guacetisal, hydrocodone, hydrocodone bitartrate, ride, hexetidine, triclosan, hydrogen peroxide, domiphen hydromorphone, hydromorphone hydrochloride, imidazole bromide, bismuth subsalicylate, loperamide hydrochloride, salicylate, ketobemidone, metamizole sodium, methadone, aluminum hydroxide, magnesium hydroxide, magnesium morphinan derivatives, morphine, morphine Sulphate pen aluminum silicate simethicone, aluminum carbonate, cal tahydrate, morphine-6-glucuronode, morpholine Salicylate, cium carbonate, Sodium bicarbonate, hydrotalcite, nalbuphine, natural opium alkaloids, nefopam, nicomor magaldrate, cimetidine, famotidine, nizatidine, ranitidine, phine, nifenaZone, non-steroidal anti-inflammatory drugs lansoprazole, omeprazole, esomeprazole, rabeprazole, pan (NSAID), norhydrocodone, noroxycodone, opioids, opium, toprazole, dexlansoprazole, diphenoxylate, dicyclomine, oripavine derivatives, oxycodeine, oxycodone, oxycodone loperamide, rifaximin, alosetron, cholestyramine, linac hydrochloride, oxymorphone, papaveretum, pentazocine, lotide, lubiprostone, methylcellulose, polycarbophil, psyl pethidine, phenacetin, phenazocine, phenaZone, phenylpip lium, mineral oil, glycerol, docusate Sodium, Sodium bicar eridine derivatives, piritramide, potassium salicylate, propa bonate, sodium phosphate, magnesium citrate, magnesium cetamol, propyphenaZone, pyrazolones, rimazolium, salicy oxide, magnesium sulfate, bisacodyl, Sennosides, Senna, lamide, Salicylic acid derivatives, Salsalate, Sodium salicyl castor oil, alclometaSone, amcinonide, beclometaSone, ate, tapentadol, tilidine, tramadol, Viminol, Ziconotide, caf betamethasone, budesonide, ciclesonide, clobetasol, clo feine, taurine, ginko biloba, glucuronolactone, inositol, nia betaSone, clocortolone, cloprednol, cortivaZol, deflazacort, cin, niacinamide, D-pantothenol, panax ginseng root extract, deoxycorticosterone, desonide desoximetasone, dexametha pyridoxine HC1, vitamin B12, cyanocobalamin, riboflavin, sone, diflorasone, diflucortolone, difluprednate, fluclo guarana, L-carnitine, vitamin A (retinol), B1 (thiamine), B2 rolone, fludrocortisone, fludroxycortide, flumetasone, fluni (riboflavin), B complex, B6 (pyridoxine), B12 (cobalamin), Solide, fluocinolone acetonide, fluocinonide, fluocortin, C (ascorbic acid), D (cholecalciferol), E (tocopherol), F fluocortolone, fluorometholone, fluperolone, fluticasone, (linoleic acid), G, H (biotin), and K, and choline, folic acid, fluticasone propionate, fluprednidene, formocortal, halcino inositol, niacin, pantothenic acid, para-aminobenzoic acid, nide, halometaSone, hydrocortisone aceponate, hydrocorti terpenoids (e.g., carotenoid terpenoids and non-carotenoid Sone buteprate, hydrocortisone butyrate, loteprednol, terpenoids), herbal Supplements, homeopathic Supplements, medrysone, meprednisone, methylprednisolone, methyl glandular supplements, polyphenolics, flavonoid polyphe prednisolone aceponate, mometasone furoate, parametha nolics, phenolic acids, curcumin, resveratrol, lignans, glu US 2016/0279056A1 Sep. 29, 2016

cosinolates, isothiocyanates, indoles, thiosulfinates, phytos 15. The composition of claim 1, wherein the shell com terols, anthraquinones, capsaicin, piperine, chlorophyll. prises: betaine, oxalic acid, acetyl-L-carnitine, allantoin, andros (a) about 35% of one or more film-forming polymers; tenediol, androstendione, betaine (trimethylglycine), caf (b) about 37% of one or more plasticizers; feine, calcium pyruvate (pyruvic acid), carnitine, carnosine, (c) about 0.5% of one or more polymer modifiers: carotene, carotenoid, choline, chlorogenic acid, cholic acid, (d) about 2.7% of one or more first sweeteners; and chondroitin Sulfate, chondroitin Sulfate, cholestan, chrysin, (e) about 21% of one or more solvents. coenzyme Q10, conjugated linoleic acid, corosolic acid, 16. The composition of claim 1, wherein the ratio of the creatine, dehydroepiandrosterone, dichlorophen, diindo active pharmaceutical ingredient to a combined weight lymethane, dimethylglycine, dimercapto Succinic acid, percentage of the hydrophilic vehicle, flavor, sweetener, ebselen, ellagic acid, enzymes, fisetin, formononetin, glu solvent and excipient is about 1:0.5 to about 1:500. caric acid (glucarate), glucosamine (HCl or Sulfate), glu 17. A method for treating, retarding the progression of cosamine (N-acetyl), glutathione, hesperidine, hydroxy-3- prophylaxis of delaying the onset of ameliorating, reducing methylbutyric acid, 5-hydroxytryptophan, indole-3- the symptoms of, or promoting health, including but not carbinol, inositol, isothiocyanates, linolenic acid-gamma, limited to of one or more of pain, inflammation, cough, cold, lipoic acid (alpha), melatonin, methylsulfonylmethane, sinusitis, throat or bronchial irritation, fever, flu, inflamma menthol, minerals, maringin, pancreatin, para-aminobenzoic tion of the gastrointestinal tract, neoplasia, hyperthyroidism, acid, paraben (methyl or propyl), phenolics, phosphatidyl hypercalcemia, hyperparathyroidism, parathyroid carci choline, phosphatidylserine, phospholipids, phytosterols, noma, indigestion, heartburn, irritable bowels, constipation, progesterone, pregnenolone, omega-3 fatty acids, quercetin, diarrhea, insomnia, dry mouth, halitosis, stained teeth, oral resveratrol, D-ribose, rutin, S-adenosylmethionine, Salicylic pain, loss of enamel, cessation of urge to Smoke, fatigue, or acid, Sulforaphane, tartaric acid, taxifolin, tetrahydropalma malaise comprising administering to a subject in need tine, theophyline, theobromine, tigogenin, troXerutin, tryp thereof the oral pharmaceutical composition of claim 1. tophan, tocotrienol (alpha, beta, and gamma), Zeaxanthin, 18. A composition for treating, retarding the progression gingko biloba, ginger, cat’s claw, hypericum, aloe Vera, of prophylaxis of delaying the onset of ameliorating, evening primrose, garlic, ginseng, Capsicum, dong quai, reducing the symptoms of, or promoting health, including ginseng, feverfew, fenugreek, echinacea, green tea, marsh but not limited to of one or more of pain, inflammation, mallow, saw palmetto, tea tree oil, fish oil, psyllium, kava cough, cold, sinusitis, throat or bronchial irritation, fever, kava, licorice root, mahonia aquifolium, hawthorne, flu, inflammation of the gastrointestinal tract, neoplasia, tumeric, witch Hazel, yohimbe, aleurain, mistletoe, bilberry, hyperthyroidism, hypercalcemia, hyperparathyroidism, bee pollen, peppermint oil, beta-carotene, genistein, lutein, parathyroid carcinoma, indigestion, heartburn, irritable lycopene, polyphenols, Bifidobacterium infantis 35624, Bifi bowels, constipation, diarrhea, insomnia, dry mouth, hali dobacterium lactis HNO19, Lactobacillus reuteri tosis, stained teeth, oral pain, loss of enamel, cessation of ATCC55730, Lactobacillus rhamnosus, Lactobacillus casei urge to Smoke, fatigue, or malaise comprising the oral DN-114 001, Bifidobacterium lactis Bb-12, or mixtures or pharmaceutical composition of claim 1. combinations thereof. 19. A pharmaceutical composition comprising a soft dos 10. (canceled) age form comprising a shell encapsulating a liquid matrix, 11. The composition of claim 1, wherein the one or more active pharmaceutical ingredients comprises one or more of wherein the shell comprises: dextromethorphan hydrobromide, menthol, thymol, nico (a) about 20% to about 60% of one or more film-forming tine, nicotine polacrilex, bismuth subsalicylate, NSAIDS, or polymers; combinations thereof. (b) about 30% to about 70% of one or more plasticizers; 12. The composition of claim 1, wherein the matrix is a (c) about 0.5% to about 2% of one or more polymer liquid, flowable gel, or viscous semi-solid. modifiers; 13. The composition of claim 1, wherein the shell com (d) about 0.1% to about 5% of one or more first sweet prises: eners; (a) about 20% to about 60% of one or more film-forming (e) about 10% to about 40% of one or more solvents; and polymers; the matrix comprises: (b) about 30% to about 70% of one or more plasticizers; about 30% to about 95% of one or more hydrophilic (c) about 0.5% to about 2% of one or more polymer vehicles; modifiers; (g) about 0.05% to about 5% of one or more second (d) about 0.1% to about 5% of one or more first Sweet Sweeteners; eners; and (h) about 0.01% to about 6% of one or more flavors; (e) about 10% to about 40% of one or more solvents. (i) about 1% to about 20% water; and 14. The composition of claim 1, wherein the matrix (j) about 0.05% to about 60% of one or more active comprises: pharmaceutical ingredients. (a) about 30% to about 95% of one or more hydrophilic 20. A method of delivering an active pharmaceutical vehicles; ingredient to a patient population unable to receive a con (b) about 0.05% to about 5% of one or more second ventional dosage form comprising administering to the Sweeteners; patient the oral pharmaceutical composition comprising the (c) about 0.01% to about 6% of one or more flavors; soft dosage form of claim 19. (d) about 1% to about 20% one or more solvents; and 21. A composition for delivering an active pharmaceutical (e) about 0.05% to about 60% of one or more active ingredient to a patient population unable to receive a con pharmaceutical ingredients. ventional dosage form comprising administering to the US 2016/0279056A1 Sep. 29, 2016 36 patient in need thereof an oral pharmaceutical composition more Sweeteners, one or more excipients, one or more comprising a soft dosage form of claim 19. active pharmaceutical ingredients in one or more sol 22. A pharmaceutical combination comprising the com Vents; position of claim 1, and one or more additional therapeutic (d) mixing the second solution at least about 50° C.; compounds. (e) casting the gel composition into films or ribbons using heat-controlled drums or Surfaces; and 23. The pharmaceutical combination of claim 22, wherein forming a soft dosage form comprising a liquid matrix fill the one or more additional therapeutic compounds com using rotary die encapsulation technology. prises one or more of NSAIDS, diphenhydramine, codeine, 26. An oral pharmaceutical composition comprising a soft chlorhexidine, cimetidine, ranitidine, famotidine, ondanse dosage form comprising an active pharmaceutical ingredient tron, omeprazole, lansoprazole, rabeprazole, esomeprazole, in a liquid matrix produced by the method of claim 25. pantoprazole, calcium Supplements, magnesium hydroxide, 27. The composition of claim 19 wherein the dosage form bupropion, or Varenicline. is stable for at 25°C. for at least one year. 24. A method for treating for treating, retarding the 28. A kit for dispensing the oral pharmaceutical compo progression of prophylaxis of delaying the onset of ame sition of claim 1, the kit comprising: liorating, reducing the symptoms of, or promoting health, (a) at least one oral pharmaceutical composition; including but not limited to of one or more of pain, inflam (b) at least one moisture proof dispensing receptacle mation, cough, cold, chest congestion, nasal congestion, comprising blister or strip packs, an aluminum blister, a transparent or opaque polymer blister with pouch, sinusitis, throat or bronchial irritation, allergies, fever, flu, polypropylene tubes, colored blister materials, tubes, inflammation of the gastrointestinal tract, Sour stomach, bottles, and bottles optionally containing a child-resis neoplasia, hyperthyroidism, hypercalcemia, hyperparathy tant feature, optionally comprising a desiccant, Such as roidism, parathyroid carcinoma, indigestion, heartburn, irri a molecular sieve or silica gel; and optionally table bowels, constipation, diarrhea, insomnia, dry mouth, (c) at least one daily regimen for the oral pharmaceutical mouth odor, halitosis, stained teeth, oral pain, loss of composition; and enamel, nicotine desire; cessation of urge to Smoke, fatigue, (d) an insert comprising instructions or prescribing infor or malaise comprising administering to a Subject in need mation for the oral pharmaceutical composition. thereof the pharmaceutical combination of combination 29. The kit of claim 28, that is useful for treating pain, claim 22. inflammation, cough, cold, chest congestion, nasal conges 25. A method for manufacturing an oral pharmaceutical tion, sinusitis, throat or bronchial irritation, allergies, fever, composition comprising the steps of flu, inflammation of the gastrointestinal tract, sour stomach, (a) preparing a gel mass composition where the compo neoplasia, hyperthyroidism, hypercalcemia, hyperparathy sition comprises one or more film forming polymers, roidism, parathyroid carcinoma, indigestion, heartburn, irri one or more plasticizers, one or more Sweeteners, one table bowels, constipation, diarrhea, insomnia, dry mouth, or more excipients in one or more solvents; mouth odor, halitosis, stained teeth, oral pain, loss of (b) mixing the first solution at least about 50° C. under enamel, nicotine desire, cessation of urge to Smoke, fatigue, vacuum for 1 to 2 hours; or malaise. (c) preparing a gel fill composition comprising one or 30-132. (canceled) more hydrophilic vehicles, one or more flavors, one or k k k k k