US 2016.0000703A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0000703 A1 Micka et al. (43) Pub. Date: Jan. 7, 2016

(54) ABUSE DETERRENT IMMEDIATE RELEASE Publication Classification FORMULATIONS COMPRISING NON-CELLULOSE POLYSACCHARDES (51) Int. Cl. 469/46 (2006.01) (71) Applicant: Mallinckrodt LLC, Hazelwood, MO A613 L/485 (2006.01) (US) A647/34 (2006.01) A647/32 (2006.01) (72) Inventors: Alex Micka, Hazelwood, MO (US); Kai A647/36 (2006.01) Feng, Hazelwood, MO (US); Tsz Chung A647/38 (2006.01) Lai, Hazelwood, MO (US); Jonathan (52) U.S. Cl. Gaik, Hazelwood, MO (US) CPC ...... A61 K9/0007 (2013.01); A61K47/36 (2013.01); A61 K47/38 (2013.01); A61K47/34 (2013.01); A61 K47/32 (2013.01); A61 K (21) Appl. No.: 14/788,908 31/485 (2013.01) (57) ABSTRACT The present disclosure provides pharmaceutical composi (22) Filed: Jul. 1, 2015 tions that provide immediate release of active ingredients and have abuse deterrent properties. In particular, the pharmaceu tical compositions comprise at least one pharmaceutically Related U.S. Application Data active ingredient, at least one non-cellulose polysaccharide, (60) Provisional application No. 62/020,726, filed on Jul. 3, at least one hydrophilic gelling polymer, and an effervescent 2014. system. US 2016/0000703 A1 Jan. 7, 2016

ABUSE DETERRENT IMMEDIATE RELEASE pharmaceutical compositions comprise non-cellulose FORMULATIONS COMPRISING polysaccharides and hydrophilic gelling polymers in combi NON-CELLULOSE POLYSACCHARDES nation with an effervescent system comprising an acid com ponent and a base component. It was unexpectedly discov CROSS-REFERENCE TO RELATED ered that the combination of non-cellulose polysaccharides, APPLICATIONS hydrophilic gelling polymers, and the effervescent system 0001. This application claims the priority of U.S. Provi makes the compositions resistant to crushing into fine pow sional Application Ser. No. 62/020,726, filed Jul. 3, 2014, the ders and/or extracting with suitable solvents at a variety of disclosure of which is hereby incorporated by reference in its temperatures, while still providing immediate release of the entirety. active ingredient(s). The present disclosure also provides pro cesses for preparing the immediate release, abuse deterrent FIELD pharmaceutical compositions disclosed herein. 0002 The present disclosure generally relates to pharma (I) Pharmaceutical Compositions ceutical compositions that provide immediate release of active ingredients and have abuse deterrent properties. 0010. One aspect of the present disclosure provides abuse deterrent pharmaceutical compositions that provide immedi BACKGROUND ate release of the active pharmaceutical ingredients. Detailed below are the components of the compositions, release char 0003. Abuse of prescription drugs (particularly opioids) acteristics of the compositions, and abuse deterrent properties has become a serious Societal problem. Such abuse places an of the compositions. enormous economic burden on Society due to increased health care, work place, and criminal justice costs. Several routes of administration are commonly attempted by abusers. (a) Components For example, the oral Solid dosage form may be crushed or 0011. The pharmaceutical compositions disclosed herein pulverized into a powder and administered intranasally (i.e., comprise at least one non-cellulose polysaccharide, at least Snorted) or dissolved in a Suitable solvent (e.g., water) and one hydrophilic gelling polymer, and an effervescent system. administered parenterally (i.e., injected intravenously). The combination of the non-cellulose polysaccharide, the 0004 Attempts have been made to diminish the abuse of hydrophilic gelling polymers, and the effervescent system opioid solid dosage forms. One approach has been to include yields a composition that has abuse deterrent properties (e.g., in the dosage form an opioid antagonist that is not orally is difficult to crush into a fine powder or extract with an active but will substantially block the analgesic effects of the aqueous solvent) but which also provides rapid and immedi opioid if one attempts to dissolve the opioid and administer it ate release of the active ingredient. parenterally. Another approach has been to include gel-form ing high molecular weight polymers that confer plasticity to (i) Non-Cellulose Polysaccharides the dosage form rendering them difficult to crush and pulver ize into a powder. These high molecular weight polymers, 0012. A variety of non-cellulose polysaccharides may be however, retard the release of the active ingredient from the included in the pharmaceutical compositions disclosed dosage forms, making them unsuitable for immediate release herein. Suitable polysaccharides include, without limit, natu formulations. ral gums, hemicelluloses (such as Xyloglucans, Xylans, and 0005 Thus, there is a need for oral solid dosage forms that mannans), pectins (e.g., derived from citrus, apples, pears provide immediate release of the active ingredient yet are gooseberries, and the like), chitins, starches (e.g., derived resistant to abuse. from corn, potato, rice, and so forth), glycogen, chrysolami narin, derivatives thereof, and combinations thereof. SUMMARY 0013. In certain embodiments, the non-cellulose polysac 0006 Among the various aspects of the present disclosure charide is a natural gum or a combination of natural gums. is a pharmaceutical composition comprising at least one Natural gums are non-cellulose polysaccharides derived from active pharmaceutical ingredient (API) or a pharmaceutically botanical sources, seaweeds, or produced via bacterial fer acceptable salt thereof, at least one non-cellulose polysaccha mentation. Non-limiting examples of plant-derived natural ride, at least one hydrophilic gelling polymer, and an effer gums include albizia gum, aloe mucilage, beta-glucan, chicle Vescent system. gum, dammar gum, fenugreek gum, glucomannan, guar gum, 0007. A further aspect of the present disclosure encom gum arabic (also called acacia gum), gum copal, gum ghatti, passes an abuse deterrent solid dosage form comprising at gum tragacanth, hakea gum, Hibiscus rosasinensis gum, least one active pharmaceutical ingredient (API) Susceptible honey locust gum, hupu gum, karayagum, khayagum, Lepi dium sativum gum, locust bean gum, mastic gum, Mimosa to abuse or a pharmaceutically acceptable salt thereof, at least scabrella gum, Mimosapudica gum, okragum, psyllium seed one natural gum, at least one hydrophilic gelling polymer, and husks (also called ispaghula husk), Spruce gum, Sterculia an effervescent system. foetida gum, tamarind gum, tara gum, and derivatives of any 0008. Other aspects and iterations of the disclosure are of the foregoing. Examples of natural gums derived from described in more detail below. seaweeds include, without limit, alginate or alginic acid, fucoidan, and laminarin derived from brown seaweeds, and DETAILED DESCRIPTION agar and carrageenans derived from red seaweeds. Non-lim 0009. The present disclosure provides pharmaceutical iting examples of natural gums produced by bacterial fermen compositions that provide rapid release of the active ingredi tation include Xanthan gum, gellangum, dextran, welangum, ents and have abuse deterrent properties. In particular, the diutan gum, pullulan, and derivatives thereof. US 2016/0000703 A1 Jan. 7, 2016

0014. In specific embodiments, the non-cellulose polysac and will vary. Non-limiting examples of suitable cellulose charide is a natural gum. In one embodiment, the non-cellu ethers include hydroxypropylcellulose (HPC), hydroxypro lose polysaccharide may be a glucomannan. Glucomannans pylmethylcellulose (HPMC), carboxymethylcellulose are linear polysaccharides composed off-1.4 linked D-man (CMC) (e.g., sodium carboxymethylcellulose), methylcellu nose and D-glucose residues (with acetyl side branches on lose, hydroxyethylcellulose, hydroxyethylmethylcellulose, some of the backbone units) that are derived from softwoods, methylhydroxyethylcellulose, and the like. In specific roots, tubers, and plant bulbs. The mannose to glucose ratio embodiments, the cellulose ether may be hydroxypropylcel depends upon the source of the glucomannan. For example, lulose, hydroxypropylmethylcellulose, sodium carboxym konjac glucomannan, which is derived from the tubers of ethylcellulose, or combinations thereof. The average molecu Amorphophallus konjac K. Koch, has a mannose:glucose lar weight of the cellulose ether may range from about 20,000 ratio of 1.6:1, whereas those extracted from Scotch pine or to about 1,500,000. In various embodiments, the weight aver orchids have ratios of 2.1:1 or 3.6:1, respectively. In a par age molecular weight of the cellulose ether may be about ticular iteration, the glucomannan may be konjac glucoman 30,000, about 100,000, about 250,000, about 850,000, or nan. In another embodiment, the non-cellulose polysaccha about 1,150,000. ride may be a combination of glucomannan and Xanthan gum. 0020. In other embodiments, the hydrophilic gelling poly 0015. In general, the non-cellulose polysaccharide has a mer may be a polyalkylene oxide such as polyethylene oxide high molecular weight and forms a viscous mixture or gel (PEO), polypropylene oxide (PPO), derivatives thereof, upon contact with water or an aqueous solution. In some copolymers thereof, or combinations thereof. In particular embodiments, the polysaccharide may have an average embodiments, the hydrophilic gelling polymer may be a poly molecular weight of greater than about 200,000, greater than ethylene oxide or a combination of polyethylene oxides of about 500,000, greater than about 1,000,000, greater than different molecular weights. The average molecular weight of about 2,000,000, or greater than about 4,000,000. the polyethylene oxide may range from about 100,000 to 0016. The amount of the non-cellulose polysaccharide about 10,000,000. In certain embodiments, the polyethylene present in the pharmaceutical composition, can and will vary oxide may have an average molecular weight of about 100, depending upon the desired properties of the pharmaceutical 000 or about 4,000,000. composition, as well as the identity and amounts of other 0021. In still other embodiments, the hydrophilic polymer components present in the dosage form. In general, the may be a polyacrylic acid. Suitable polyacrylic acids include amount of non-cellulose polysaccharide in the composition carbomers, which are homopolymers of acrylic acid cross may range from about 2% to about 60% by weight of the linked with polyalcohol allyl ethers (e.g., allyl ether pen pharmaceutical composition. In various embodiments, the taerythritol, allyl ether of sucrose, orallyl ether of propylene), amount of the non-cellulose polysaccharide may range from and polycarbophil, which is a homopolymer of acrylic acid about 3% to about 50%, from about 5% to about 40%, from cross linked with divinylglycol. Available carbomers include about 6% to about 30%, or from about 10% to about 25% by Carbopol 910, 934,940, 941, and 943P (the codes are indi weight of the pharmaceutical composition. In some embodi cators of molecular weight and the specific components of the ments, the amount of non-cellulose polysaccharide may polymer). range from 2% to about 10%, from about 10% to about 15%, 0022. In additional embodiments, the hydrophilic gelling from about 15% to about 20%, from about 20% to about 25%, polymer may be a polyamine Such as polyethyleneimine, from about 25% to about 40%, or from about 40% to about polyvinylamine, or the like. In still further embodiments, the 60% by weight of the pharmaceutical composition. In par hydrophilic gelling polymer may be a polyolefinic alcohol ticular embodiments, the amount of non-cellulose polysac (such as polyvinyl alcohol), or a polyvinyl lactam (such as, charide may be about 25% or less by weight of the pharma e.g., polyvinylpyrrolidone, polyvinyl caprolactam, and the ceutical composition. In specific embodiments, the amount of like). The average molecular weight of said polymers may non-cellulose polysaccharide in the composition may range range from about 20,000 to about 1,300,000. from about 5% to about 40% by weight of the pharmaceutical 0023. In specific embodiments, the hydrophilic gelling composition. polymer may comprise a combination of one or more cellu lose ethers (e.g., hydroxypropylcellulose, hydroxypropylm (ii) Hydrophilic Gelling Polymers ethylcellulose, sodium carboxymethylcellulose) and one or 0017. The pharmaceutical compositions disclosed herein more polyethylene oxides having different molecular also comprise at least one hydrophilic gelling polymer. The weights. term “hydrophilic gelling polymer refers to a polymer with 0024. The amount of the hydrophilic gelling polymer affinity for water such that it readily absorbs water or an present in the pharmaceutical composition can and will vary aqueous solution and/or Swells when in contact with water or depending upon the desired properties of the pharmaceutical an aqueous Solution to form a viscous mixture or gel. composition, as well as the identity and amounts of other 0018. A variety of hydrophilic gelling polymers are suit components present in the pharmaceutical composition. In able for use in the pharmaceutical Solid dosage forms. The general, the amount of the hydrophilic gelling polymer may polymer may be natural, semi-synthetic, or synthetic. Non range from about 5% to about 80% by weight of the pharma limiting examples of Suitable hydrophilic gelling polymers ceutical composition. In various embodiments, the amount of include cellulose ethers, polyalkylene oxides, polyacrylic the hydrophilic gelling polymer in the composition may acids, polyamines, polyolefinic alcohols, polyvinyl lactams, range from about 6% to about 70%, from about 8% to about derivatives thereof, and combinations thereof. 60%, from about 10% to about 50%, from about 15% to about 0019. In some embodiments, the hydrophilic gelling poly 40%, or from about 20% to about 35% by weight of the mer may be a cellulose ether. Cellulose ethers are cellulose pharmaceutical composition. In certain embodiments, the derivatives in which the hydrogen atoms of hydroxyl groups amount of the hydrophilic gelling polymer may range from are replaced with alkyl groups. The degree of substitution can about 5% to about 20%, from about 20% to about 25%, from US 2016/0000703 A1 Jan. 7, 2016

about 25% to about 30%, from about 30% to about 40%, from Non-limiting examples of Suitable bases include ammonium about 40% to about 60%, or from about 60% to about 80% by bicarbonate, calcium bicarbonate, lithium bicarbonate, mag weight of the pharmaceutical composition. In specific nesium bicarbonate, potassium bicarbonate, Sodium bicar embodiments, the amount of the hydrophilic gelling polymer bonate, arginine carbonate, ammonium carbonate, calcium may range from about 10% to about 50% by weight of the carbonate, lysine carbonate, potassium magnesium carbon pharmaceutical composition. ate, Sodium carbonate, sodium glycine carbonate, sodium sesquicarbonate, Zinc carbonate, and combinations thereof. (iii) Effervescent System In exemplary embodiments, the base may be an alkali metal 0025. The pharmaceutical composition disclosed herein bicarbonate. In one exemplary embodiment, the base may be also comprises an effervescent system. As used herein, an Sodium bicarbonate. In another exemplary embodiment, the “effervescent system” refers to a system generally compris base may be heat-treated sodium bicarbonate (for example ing an acid component and a base component, wherein the EfferSoda(R) 12). system liberates carbon dioxide upon contact with an aqueous 0029. The mole to mole ratio of the acid component to the solution. Without being bound by any particular theory, it is base component in the effervescent system may also vary believed that the effervescent system facilitates rapid disso depending, for example, upon the identity of the acid and the lution of the API from the composition comprising the com base. In general, the mole to mole ratio of the acid component bination of non-cellulose polysaccharide(s) and hydrophilic to the base component in the effervescent system may range gelling polymer(s). from about 1:0.2 to about 1:5. For example, the mole to mole 0026. The acid component of the effervescent system may ratio of the acid component to the base component in the be an organic acid, an inorganic acid, or a combination effervescent system may be about 1:0.2, about 1:0.25, about thereof. Non-limiting examples of suitable acids include adi 1:0.33, about 1:0.5, about 1:1, about 1:2, about 1:3, about 1:4, pic acid, ascorbic acid, benzoic acid, citric acid, fumaric acid, about 1:5 or any ratio in between. In one exemplary embodi glutaric acid, lactic acid, lauric acid, malic acid, maleic acid, ment, the mole to mole ratio of the acid component to the base malonic acid, oxalic acid, phthalic acid, Sorbic acid, Succinic component in the effervescent system may range from about acid, tartaric acid, ammonium phosphate, potassium bitar 1:1 to about 1:3. In another exemplary embodiment, the mole trate, potassium phosphate, dipotassium phosphate, disodium to mole ratio of the acid component to the base component in pyrophosphate, sodium acid pyrophosphate, sodium phos the effervescent system may be about 1:2. phate, disodium phosphate, and combinations thereof. In spe 0030 The amount of the effervescent system present in the cific embodiments, the acid component of the effervescent pharmaceutical composition can and will vary depending system may be an organic acid. In one iteration, the acid upon the identity of the other components and the desired component may be tartaric acid. In other embodiments, the properties of the pharmaceutical composition. In general, the acid component of the effervescent system may be an inor amount of the effervescent system may range from about 20% ganic acid. to about 90% by weight of the pharmaceutical composition. 0027. In some embodiments, the acid component of the In various embodiments, the amount of the effervescent sys effervescent system may be co-processed with a polyalkylene tem in the composition may range from about 20% to about glycol (such as, e.g., polyethylene glycol), a poloxamer 80%, from about 25% to about 70%, from about 30% to about (which is a difunctional, tri-block copolymer of polyethylene 60%, or from about 40% to about 50% by weight of the oxide and polypropylene oxide), or combinations thereof. pharmaceutical composition. In certain embodiments, the Non-limiting examples of Suitable polyethylene glycols amount of the effervescent system may range from about 20% to about 30%, from about 30% to about 40%, from about 40% (PEG) include PEG 1000, PEG 2000, PEG 3300, PEG 4000, to about 50%, from about 50% to about 60%, from about 60% PEG 5000, PEG 6000, PEG 8000, PEG 10,000, PEG 20,000, to about 70%, from about 70% to about 80%, or from about PEG 30,000, derivatives thereof, copolymers thereof, and 80% to about 90% by weight of the pharmaceutical compo combinations thereof. Examples of suitable poloxamers sition. In specific embodiments, the amount of the efferves (which are available under the trade names KOLLIPHORTM cent system may range from about 30% to about 60% by or PLURONICR) include, without limit, Poloxamer 101, weight of the pharmaceutical composition. 105, 108, 122, 123, 124, 181, 182, 183, 184, 185, 188,212, 215, 217, 231, 234, 235, 237,238, 282, 284, 288,331, 333, 334, 335, 338, 401, 402, 403, and 407, wherein the first two (iv) Additional Components digits multiplied by 100 give the approximate molecular mass 0031. In some embodiments, the pharmaceutical compo and the last digit multiplied by 10 gives the percentage of the sition disclosed herein may also comprise a lubricant. Non polyoxyethylene oxide content. The acid and the polyalky limiting examples of Suitable lubricants include metal Stear lene glycol and/or poloxamer may be co-processed by a vari ate Such as magnesium Stearate, calcium Stearate, Zinc ety of means including, without limit, hot melt granulation, Stearate, a polyethylene glycol, apoloxamer, colloidal silicon fluidized hot melt granulation, hot melt mixing, wet granula dioxide, glyceryl behenate, light mineral oil, hydrogenated tion, liquid spray mixing, and the like. The amount of poly Vegetable oils, magnesium lauryl Sulfate, magnesium trisili alkylene glycol and/or poloxamer co-processed with the acid cate, polyoxyethylene monostearate, sodium Stearoyl fuma can and will vary. In general, the weight to weight ratio of the rate, Sodium Stearyl fumarate, Sodium benzoate, sodium lau acid to the polyalkylene glycol and/or poloxamer may range ryl Sulfate, Stearic acid, Sterotex, talc, and combinations from about 1:0.01 to about 1:0.5. thereof. In specific embodiments, the lubricant may be a 0028. The base component of the effervescent system may metal Stearate. In one iteration, the lubricant may be magne be a bicarbonate, a carbonate, or a combination thereof. In sium Stearate. various embodiments, the base may be an alkali metal bicar 0032. The amount of lubricant present in the pharmaceu bonate, an alkaline earth metal bicarbonate, an alkali metal tical composition can and will vary depending upon the iden carbonate, an organic carbonate, or combinations thereof. tities and amounts of other components in the composition. In US 2016/0000703 A1 Jan. 7, 2016

embodiments in which a lubricant is present, the amount of mopan, cyprodime, diprenorphine, gemazocine, lubricant generally ranges from about 0.1% to about 3% by 5'-guanidinonaltrindole, levallorphan, methylmaltrexone, weight of the pharmaceutical composition. In various naldemedine, nalmexone, nalorphine, naloxazone, naloxol. embodiments, the amount of lubricant present in the compo naloxonazine, 6B-maltrexol-d4, maltriben, naltrindole, norb sition may range from about 0.1% to about 0.3%, from about inaltorphimine, oxilorphan, quadazocine, and Samidorphan); 0.3 to about 1%, or from about 1% to about 3% by weight of non-opioid analgesic agents (e.g., acetylsalicylic acid, the composition. In specific embodiments, the amount of acetaminophen, paracetamol, ibuprofen, ketoprofen, lubricant present in the composition may range from about indomethacin, diflunisol, naproxen, ketorolac, dichlophenac, 0.2% to about 2% by weight of the pharmaceutical composi tolmetin, Sulindac, phenacetin, piroXicam, and mefamanic tion. In one specific embodiment, the amount of lubricant present in the composition may range from about 0.3% to acid); anti-inflammatory agents (e.g., glucocorticoids such as about 1% by weight of the pharmaceutical composition. alclometaSone, fluocinonide, methylprednisolone, triamci 0033. In additional embodiments, the pharmaceutical nolone and dexamethasone; non-steroidal anti-inflammatory composition disclosed herein may also comprise a preserva agents such as celecoxib, deracoxib, ketoprofen, lumira coxib, meloxicam, parecoxib, rofecoxib, and Valdecoxib); tive. Non limiting examples of suitable preservatives include antitussive agents (e.g., dextromethorphan, codeine, hydroc antioxidants (such as, e.g., alpha-tocopherol, ascorbyl palmi odone, caramiphen, carbetapentane, and dextromethorphan); tate, butylated hydroxyanisole, butylated hydroxytoluene, antipyretic agents (e.g., acetylsalicylic acid and acetami citric acid, dihydroguaretic acid, potassium ascorbate, potas nophen); antibiotic agents (e.g., aminoglycosides Such as, sium Sorbate, propylgallate, Sodium bisulfate, sodium amikacin, gentamicin, kanamycin, neomycin, netilmicin, isoascorbate, sodium metabisulfate, Sorbic acid, 4-chloro-2, streptomycin, and tobramycin; carbecephem Such as loracar 6-ditertiarybutylphenol, and so forth), antimicrobials (such bef carbapenems such as certapenem, imipenem, and mero as, e.g., benzyl alcohol, cetylpryidine chloride, glycerine, penem; cephalosporins such as cefadroxil cefazolin, cephal parabens, propylene glycol, potassium Sorbate, sodium ben exin, cefaclor, cefamandole, cephalexin, cefoxitin, cefprozil, Zoate, Sorbic acid, sodium propionate, and the like), and com cefuroxime, cefixime, cefdinir, cefditoren, cefoperaZone, binations thereof. In specific embodiments, the preservative cefotaxime, cefpodoxime, ceftazidime, ceftibuten, cefti may be butylated hydroxytoluene, citric acid, or a combina Zoxime, and ceftriaxone; macrollides such as azithromycin, tion thereof. clarithromycin, dirithromycin, erythromycin, and troleando 0034. The amount of preservative present in the pharma mycin; monobactam, penicillins such as amoxicillin, ampi ceutical composition can and will vary. In embodiments in cillin, carbenicillin, cloxacillin, dicloxacillin, nafcillin, which a preservative is present, the amount of preservative in oxacillin, penicillin G, penicillin V, piperacillin, and ticarcil the composition may range from about 0.005% to about 3% lin; polypeptides Such as bacitracin, colistin, and polymyxin by weight of the pharmaceutical composition. In various B; quinolones such as ciprofloxacin, enoxacin, gatifloxacin, embodiments, the amount of preservative may range from levofloxacin, lomefloxacin, moxifloxacin, norfloxacin, about 0.005% to about 0.03%, from about 0.03 to about 0.1%, ofloxacin, and trovafloxacin; Sulfonamides such as mafenide, from about 0.1% to about 0.3%, from about 0.3% to about Sulfacetamide, Sulfamethizole, SulfaSalazine, Sulfisoxazole, 1.0%, or from about 1% to about 3% by weight of the com and trimethoprim-sulfamethoxazole; tetracyclines such as position. In specific embodiments, the amount of preservative demeclocycline, doxycycline, minocycline, and oxytetracy may range from about 0.01% to about 1% by weight of the cline); antimicrobial agents (e.g., ketoconazole, amoxicillin, pharmaceutical composition. cephalexin, miconazole, econazole, acyclovir, and nelfi navir); antiviral agents (e.g., acyclovir, gangciclovir, oselta (v) API mivir, and relenza); steroids (e.g., estradiol, testosterone, cor 0035. The pharmaceutical composition disclosed herein tisol, aldosterone, prednisone, and cortisone); amphetamine comprises at least one API or a pharmaceutically acceptable stimulant agents (e.g., amphetamine and amphetamine-like salt thereof. Suitable APIs include, without limit, opioid anal drugs); non-amphetamine stimulant agents (e.g., meth gesic agents (e.g., adulmine, alfentanil, allocryptopine, allyl ylphenidate, nicotine, and caffeine); laxative agents (e.g., prodine, alphaprodine, anilleridine, aporphine, benzylmor bisacodyl, casanthranol, Senna, and castor oil); anti-nausea phine, berberine, bicuculine, bicucine, bezitramide, agents (e.g., dolasetron, granisetron, ondansetron, tro buprenorphine, bulbocaprine, butorphanol, clonitaZene, pisetron, meclizine, and cyclizine); anorexic agents (e.g., fen codeine, desomorphine, dextromoramide, dezocine, diam fluramine, dexfenfluramine, mazindol, phentermine, and promide, diamorphone, dihydrocodeine, dihydromorphine, aminorex); antihistaminic agents (e.g., phencarol, cetirizine, dimenoxadol, dimepheptanol, dimethylthiambutene, diox cinnarizine, ethamidindole, azatadine, brompheniramine, aphetylbutyrate, dipipanone, eptazocine, ethoheptazine, eth hydroxy Zine, and chlorpheniramine); antiasthmatic agents ylmethylthiambutene, ethylmorphine, etonitaZene, fentanyl. (e.g., Zileuton, montelukast, omalizumab, fluticaSone, and heroin, hydrocodone, hydromorphone, hydroxypethidine, Zafirlukast); antidiuretic agents (e.g., desmopressin, vaso isomethadone, ketobemidone, levorphanol, levophenacyl pressin, and lypressin); anti migraine agents (e.g., naratrip morphan, lofentanil, meperidine, meptazinol, metazocine, tan, froVatriptan, eletriptan, dihydroergotamine, Zolmitriptan, methadone, metopon, morphine, myrophine, narceline, nico almotriptan, and Sumatriptan); antispasmodic agents (e.g., morphine, norlevorphanol, normethadone, nalorphine, nal dicyclomine, hyoscyamine, and peppermint oil); antidiabetic buphine, nalmefene, normorphine, norpipanone, opium, oxy agents (e.g., methformin, acarbose, miglitol, pioglitaZone, codone, Oxymorphone, papaveretum, pentazocine, rosiglitaZone, nateglinide, repaglinide, mitiglinide, saxaglip phenadoxone, phenomorphan, phenazocine, phenoperidine, tin, Sitagliptine, Vildagliptin, acetohexamide, chlorpropam piminodine, piritramide, propheptazine, promedol, properi ide, gliclazide, glimepiride, glipizide, glyburide, tolaZamide, dine, propoxyphene, Sufentanil, tapentadol, tilidine, and tra and tolbutamide); respiratory agents (e.g., albuterol, ephe madol); opioid antagonists (e.g., naloxone, naltrexone, alvi drine, metaproterenol, and terbutaline); sympathomimetic US 2016/0000703 A1 Jan. 7, 2016 agents (e.g., pseudoephedrine, phenylephrine, phenylpro any suitable form, such as, for example, as a pharmaceutically panolamine, epinephrine, norepinephrine, dopamine, and acceptable salt, uncharged or charged molecule, molecular ephedrine); H2 blocking agents (e.g., cimetidine, famotidine, complex, Solvate or hydrate, prodrug, and, if relevant, isomer, nizatidine, and ranitidine); antihyperlipidemic agents (e.g., enantiomer, racemic mixture, and/or mixtures thereof. Fur clofibrate, cholestyramine, colestipol, fluvastatin, atorvasta thermore, the API may be in any of its crystalline, semi tin, genfibrozil, lovastatin, niacin, pravastatin, fenofibrate, crystalline, amorphous, or polymorphous forms. colesevelam, and simvastatin); antihypercholesterol agents 0037. In one embodiment, the API in the pharmaceutical (e.g., lovastatin, simvastatin, pravastatin, fluvastatin, atorvas composition may have a potential for abuse. For example, the tatin, cholestyramine, colestipol, colesevelam, nicotinic acid, API may be an opioid analgesic agent, a stimulant agent, a gemfibrozil, and eZetimibe); cardiotonic agents (e.g., digi sedative agent, a hypnotic agent, an antianxiolitic agent, or a talis, ubidecarenone, and dopamine); vasodilating agents muscle relaxing agent. (e.g., nitroglycerin, captopril, dihydralazine, diltiazem, and isosorbide dinitrate); vasoconstricting agents (e.g., dihydro 0038. In another embodiment, the API in the pharmaceu ergotoxine and dihydroergotamine); anticoagulants (e.g., tical composition may be a combination of an opioid analge warfarin, heparin, and Factor Xa inhibitors); sedative agents sic and a non-opioid analgesic. Suitable opioid and non (e.g., amobarbital, pentobarbital, secobarbital, clomethiaz opioid analgesics are listed above. ole, diphenhydramine hydrochloride, and alprazolam); hyp 0039. In a further embodiment, the API in the pharmaceu notic agents (e.g., Zaleplon, Zolpidem, esZopiclone, Zopi tical composition may be a combination of an opioid analge clone, chloral hydrate, and clomethiazole); anticonvulsant sic and an opioid antagonist, examples of which are listed agents (e.g., lamitrogene, oxycarbameZine, phenytoin, above. mephenytoin, ethoSuximide, methSuccimide, carbam 0040. In a specific embodiment, the API in the pharma azepine, valproic acid, gabapentin, topiramate, felbamate, ceutical composition may be an opioid analgesic. Exemplary and phenobarbital); muscle relaxing agents (e.g., baclofen, opioid analgesics include oxycodone, oxymorphone, hydro carisoprodol, chlorZOXaZone, cyclobenzaprine, dantrolene codone, hydromorphone, codeine, and morphine. In one spe Sodium, metaxalone, orphenadrine, pancuronium bromide, cific embodiment, the API may be oxycodone hydrochloride. and tizanidine); antipsychotic agents (e.g., phenothiazine, In another specific embodiment, the API may be oxymor chlorpromazine, fluphenazine, perphenazine, prochlorpera phone hydrochloride. Zine, thioridazine, trifluoperazine, haloperidol, droperidol. pimozide, clozapine, olanzapine, risperidone, quetiapine, 0041. The amount of the API in the pharmaceutical com Ziprasidone, melperone, and paliperidone); antianxiolitic position can and will vary depending upon the active agent. In agents (e.g., lorazepam, alprazolam, clonazepam, diazepam, embodiments in which the API is an opioid analgesic, the buspirone, meprobamate, and flunitrazepam); antihyperac amount of opioid in the pharmaceutical composition may tive agents (e.g., methylphenidate, amphetamine, and dextro range from about 2 mg to about 160 mg. In various embodi amphetamine); antihypertensive agents (e.g., alpha-methyl ments, the amount of opioid in the pharmaceutical composi dopa, chlortalidone, reserpine, Syrosingopine, rescinnamine, tion may range from about 2 mg to about 10 mg, from about prazosin, phentolamine, felodipine, propanolol, pindolol. 10 mg to about 40 mg, from about 40 mg to about 80 mg. or labetalol, clonidine, captopril, enalapril, and lisonopril); anti from about 80 mg to about 160 mg. In certain embodiments, neoplasia agents (e.g., taxol, actinomycin, bleomycin A2, the amount of opioid in the pharmaceutical composition may mitomycin C, daunorubicin, doxorubicin, epirubicin, idaru be about 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 bicin, and mitoxantrone); Soporific agents (e.g., Zolpidem mg, 22.5 mg, 25 mg, 27.5 mg, 30 mg. 32.5 mg, 35 mg, 37.5 tartrate, esZopiclone, ramelteon, and Zaleplon); tranquilizer mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 100 mg, 120 agents (e.g., alprazolam, clonazepam, diazepam, fluni mg, 140 mg, or 160 mg. trazepam, lorazepam, triazolam, chlorpromazine, fluiphena 0042. In embodiments in which the opioid is oxycodone Zine, haloperidol, loxapine Succinate, perphenazine, prochlo hydrochloride, the total amount of oxycodone hydrochloride rperazine, thiothixene, and trifluoperazine); decongestant present in the pharmaceutical composition may range from agents (e.g., ephedrine, phenylephrine, naphazoline, and tet about 2 mg to about 80 mg. In certain embodiments, the rahydrozoline); beta blockers (e.g., levobunolol, pindolol. amount of oxycodone hydrochloride in the pharmaceutical timolol maleate, bisoprolol, carvedilol, and butoxamine); composition may range from about 2 mg to about 10 mg, from alpha blockers (e.g., doxazosin, praZosin, phenoxyben about 10 mg to about 30 mg. or from about 30 mg to about 80 Zamine, phentolamine, tamsulosin, alfuZosin, and teraZosin); mg. In specific embodiments, the amount of oxycodone non-steroidal hormones (e.g., corticotropin, vasopressin, hydrochloride present in the pharmaceutical composition oxytocin, insulin, oxendolone, thyroid hormone, and adrenal may be about 5 mg, about 10 mg, about 15 mg, about 20 mg. hormone); erectile disfunction improvement agents; herbal about 30 mg, about 40 mg, about 60 mg, or about 80 mg. agents (e.g., glycyrrhiza, aloe, garlic, nigella sativa, rauwol 0043. In embodiments in which the opioid is oxymor fia, St John’s wort, and Valerian); enzymes (e.g., lipase, pro phone hydrochloride, the total amount of oxymorphone tease, amylase, lactase, lysozyme, and urokinase); humoral hydrochloride present in the pharmaceutical composition agents (e.g., prostaglandins, natural and synthetic, for may range from about 2 mg to about 80 mg. In certain example, PGE1, PGE2alpha, PGF2alpha, and the PGE1 ana embodiments, the amount of oxymorphone hydrochloride log misoprostol); psychic energizers (e.g., 3-(2-aminopropyl) present in the pharmaceutical composition may range from indole and 3-(2-aminobutyl)indole); nutritional agents; about 2 mg to about 10 mg, from about 10 mg to about 30 mg. essential fatty acids; non-essential fatty acids; vitamins; min or from about 30 mg to about 80 mg. In specific embodiments, erals; and combinations thereof. the amount of oxymorphone hydrochloride present in the 0036) Any of the above-mentioned APIs may be incorpo pharmaceutical composition may be about 5 mg, about 10 rated in the pharmaceutical composition described herein in mg, about 20 mg, about 30 mg, or about 40 mg. US 2016/0000703 A1 Jan. 7, 2016

(vi) Optional Excipients 0051. In a further embodiment, the optional excipient may be a flavoring agent. Flavoring agents may be chosen from 0044. In various embodiments, the pharmaceutical com synthetic flavor oils and flavoring aromatics and/or natural positions disclosed herein may further comprise at least one oils, extracts from plants, leaves, flowers, fruits, and combi additional pharmaceutically acceptable excipient. Non-lim nations thereof. iting examples of Suitable excipients include clay minerals, 0052. In still another embodiment, the optional excipient binders, fillers, diluents, disintegrants, chelating agents, fla may be a coloring agent. Suitable color additives include Voring agents, coloring agents, taste masking agents, and food, drug and cosmetic colors (FD&C), drug and cosmetic combinations thereof. colors (D&C), or external drug and cosmetic colors (Ext. 0045. In one embodiment, the optional excipient may be a D&C). clay mineral. A clay mineral refers to a hydrated aluminum 0053. In yet another embodiment, the optional excipient phyllosilicate or a hydrated magnesium silicate comprising may be a taste-masking agent. Taste-masking materials Small insoluble particles. Mixing a clay mineral with a Suit include, but are not limited to, cellulose ethers, polyethylene able solvent forms a colloidal dispersion of small particles glycols, polyvinyl alcohol, polyvinyl alcohol and polyethyl that do not sediment. Non-limiting examples of suitable clay ene glycol copolymers, monoglycerides or triglycerides, minerals include talc, bentonites, kaolinites, nontronites, acrylic polymers, mixtures of acrylic polymers with cellulose montmorillonites, pyrophyllites, Saponites, sauconites, ver ethers, cellulose acetate phthalate, and combinations thereof. miculites, and combinations thereof. In one iteration, the clay 0054 The amount of the one or more additional excipients mineral may be powdered talc or micronized talc. in the pharmaceutical Solid dosage form can and will vary 0046. In a further embodiment, the optional excipient may depending upon the identity of the excipient and the identities be a binder. Suitable binders include, but are not limited to, and amounts of the other components of the pharmaceutical starches, pregelatinized starches, gelatin, polyvinylpyroli composition. done, cellulose, methylcellulose, Sodium carboxymethylcel lulose, ethylcellulose, polyacrylamides, polyvinylalcohols, (vii) Optional Film Coating C12-C18 fatty acid alcohols, polyethylene glycols, polyols, saccharides, oligosaccharides, polypeptides, peptides, and 0055. In embodiments in which the pharmaceutical com combinations thereof. position is an oral Solid dosage form, the Solid dosage form 0047. In another embodiment, the optional excipient may may further comprise a water-soluble film coating. Typically, be a filler. Suitable fillers include, without limit, calcium the film coating comprises at least one hydrophilic polymer, carbonate, calcium phosphate, calcium Sulfate, calcium sili and the coating does not affect the immediate release or abuse cate, magnesium carbonate, magnesium oxide, sodium chlo deterrent properties of the pharmaceutical composition. The ride, starch, modified starches, cellulose, microcrystalline film coating may provide moisture protection, enhanced cellulose. Sucrose, lactose, dextrose, mannitol, Sorbitol, talc, appearance, increased mechanical integrity, improved Swal and combinations thereof. lowability, improved taste, and/or masking of odors. 0048. In another embodiment, the optional excipient may 0056 Film coatings are well known in the art, e.g., some be a diluent. Non-limiting examples of diluents suitable for are commercially available under the tradename OPADRYR). use include pharmaceutically acceptable saccharides such as Typically, a film coating comprises at least one hydrophilic Sucrose, dextrose, lactose, microcrystalline cellulose, cellu polymer and at least one plasticizer. Non-limiting examples lose, cellulose derivatives, starches, fructose, Xylitol, and Sor of suitable polymers include hydroxypropylmethylcellulose, bitol, polyhydric alcohols, pre-manufactured direct compres hydroxypropylcellulose, hydroxypropylethylcellulose, eth sion diluents, and mixtures of any of the foregoing. ylcellulose, methylcellulose, cellulose acetate phthalate, 0049. In a further embodiment, the optional excipient may microcrystalline cellulose and carrageenan, acrylic poly be a disintegrant. Examples of Suitable disintegrants include, mers, polyvinyl alcohol, anionic and cationic polymers of without limit, crospovidone, croScarmellose Sodium, sodium methacrylic acid, copolymers of methacrylates, copolymers carboxymethylcellulose, carboxymethylcellose calcium, of acrylates and methacrylates, copolymers of ethacrylate Sodium starch glycolate, cellulose, microcrystalline cellu and methylmethacrylate, polyvinylacetate phthalate, and lose, methylcellulose, silicon dioxide (also called colloidal shellac. Examples of suitable plasticizers include, without silicone dioxide), alginates, clays, and combinations of any of limit, triethyl citrate (TEC), acetyltriethyl citrate (ATEC), the foregoing. acetyl tri-n-butyl citrate (ATBC), dibutyl sebacate, diethyl phthalate, and triacetin. The film coating may optionally 0050. In an alternate embodiment, the optional excipient may be a chelating agent. Non-limiting examples of Suitable comprise additional agents such as a coloring agent, a filler, a chelating agents include ethylenediamine tetracetic acid flavoring agent, a taste-masking agent, a Surfactant, an anti (EDTA) and its salts, N-(hydroxy-ethyl)ethylenediaminetri tacking agent, and/or an anti-foaming agent. Suitable acetic acid, nitrilotriacetic acid (NIA), ethylene-bis(oxyeth examples of these agents are well known in the art and/or are ylene-nitrilo) tetraacetic acid, 1,4,7,10-tetraazacyclodo-de detailed above. cane-N,N',N',N'-tetraacetic acid, 1,4,7,10-tetraaza cyclododecane-N,N',N'-triacetic acid, 1,4,7-tris (viii) Specific Embodiments (carboxymethyl)-10-(2-hydroxypropyl)-1,4,7,10 0057. In specific embodiments, the pharmaceutical com tetraaZocyclodecane, 1,4,7-triazacyclonane-N,N',N'- position comprises from about 5% to about 40% by weight of triacetic acid, 14.8, 11-tetraazacyclotetra-decane-N,N',N', a non-cellulose polysaccharide chosen from glucomannan, N"-tetraacetic acid; diethylenetriamine-pentaacetic acid xanthan gum, or combinations thereof; from about 10% to (DTPA), ethylenedicysteine, bis(aminoethanethiol)carboxy about 50% by weight of a hydrophilic gelling polymer chosen lic acid, triethylenetetraamine-hexaacetic acid, and 1,2-di from polyethylene oxide, hydroxypropylmethylcellulose, aminocyclohexane-N,N,N',N'-tetraacetic acid. hydroxypropylcellulose, Sodium carboxymethyl cellulose, or US 2016/0000703 A1 Jan. 7, 2016

combinations thereof; from about 30% to about 60% by Solution. In other embodiments, the pharmaceutical compo weight of an effervescent system comprising an organic acid sition may have an average release of about 50%, 55%, 60%, and an alkali metal bicarbonate; and an API chosen from 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% of the API oxycodone, oxymorphone, hydrocodone, hydromorphone, within 30 minutes in the dissolution solution. codeine, or morphine. (d) Abuse Deterrent Properties 0064. The solid dosage pharmaceutical compositions dis (b) Dosage Forms closed herein also have abuse deterrent features. The combi 0058. The physical form of the pharmaceutical composi nation of non-cellulose polysaccharide(s) and hydrophilic tion disclosed herein can and will vary. In general, the phar gelling polymers along with the effervescent system imparts Sufficient mechanical integrity (i.e., strength, hardness, etc.) maceutical composition is a solid dosage form that is formu to a solid dosage composition Such the composition is resis lated for oral administration. The solid dosage form may be tant to crushing, grinding, cutting, or pulverizing to form a one of various Solid dosage units. Non-limiting examples of powder comprising Small particles. Additionally, because of Suitable Solid dosage units include tablets, compacts, pellets, the presence of the non-cellulose polysaccharide(s) and the caplets, pills, and capsules. Such dosage units may be pre hydrophilic gelling polymer(s), a viscous mixture or gel pared using conventional methods known to those in the field forms when the Solid dosage composition (or fractions of pharmaceutical formulation and described in pertinent thereof) is contacted with a small volume of a suitable solvent texts, e.g., in Gennaro, A. R., editor. “Remington: The Sci at a variety of temperatures. ence & Practice of Pharmacy’. 21st ed., 2006, Williams & 0065. The mechanical integrity of the solid dosage phar Williams, and in the “Physician's Desk Reference', 66" ed., maceutical composition may be assessed by measuring the 2014, PDR Staff. hardness or crushing strength of the Solid dosage composi 0059. In specific embodiments, the solid dosage unit may tion. The hardness of the solid dosage composition may be be a tablet. Non-limiting types of tablets include coated tab measured using any of numerous hardness testers, which are lets, uncoated tablets, compressed tablets, compacted tablets, well known in the art. In general, the Solid dosage composi molded tablets, layered tablets, bilayer tablets, extruded tab tion has a hardness or crushing strength of at least 10 kilopond lets, multiparticulate tablets, monolithic tablets, and matrix (kp). In various embodiments, the Solid dosage composition tablets. may have a hardness or crushing strength ranging from about 10 kp to about 20 kp, from about 20 kp to about 30 kp, from 0060. In embodiments in which the solid dosage form is a about 30 kp to about 40 kp, or more than about 40 kp. In tablet, the tablet generally has a friability of no greater than certain embodiments, the hardness or crushing strength of about 1.0%. In certain embodiments, the tablet may have a Solid dosage composition is less than about 50 kp. friability of less than about 1.0%, less than about 0.5%, less 0066. The mechanical integrity of the solid dosage phar than about 0.3%, less than about 0.2%, less than about 0.1%, maceutical composition also may be assessed by measuring less than about 0.05%, or less than about 0.01%. In exemplary the particle size distribution after crushing, grinding, or pull embodiments, the tablet has a friability of Zero. Verizing the composition in a Suitable apparatus for a speci fied period of time. The Solid dosage composition may be (c) In Vitro Release Properties ground or milled in a coffee grinder, a spice grinder, a nut grinder, a coffee mill, a blender, a high-shear mill, a ball mill, 0061 The pharmaceutical composition disclosed herein is a co-mill, a pill crusher, a tablet grinder, or another grinding/ formulated such that the API is released rapidly from the milling apparatus. In some embodiments, more than about composition. Thus, the composition is termed an immediate 10%, more than about 20%, more than about 30%, more than release pharmaceutical composition. As used herein, “imme about 40%, or more than about 50% of the particles formed diate release' refers to an average release of at least 70% of when the Solid dosage composition is Subjected to 6 minutes the API within 45 minutes using a USP approved in vitro of milling in a coffee grinder or high shear mill have an release test. Unlike many immediate release compositions, average diameter of greater than about 250 microns. In other the pharmaceutical composition disclosed herein comprises a embodiments, more than about 10%, more than about 20%, blend of high molecular weight non-cellulose polysaccharide more than about 30%, more than about 40%, or more than (s) and hydrophilic gelling polymer(s). The disclosed com about 50% of the particles formed when the solid dosage position, however, also comprises an effervescent system that composition is Subjected to 3 minutes of milling in a coffee facilitates ready dissolution of the composition and rapid grinder or high shear mill have an average diameter of greater release of the API from the composition. than about 250 microns. Because the Solid dosage pharma 0062. The in vitro dissolution of the API from the phar ceutical composition disclosed herein is resistant to forming maceutical composition disclosed herein may be measured a fine powder by crushing, grinding or pulverizing, it deters using an approved USP procedure. For example, dissolution abuse by inhalation. may be measured using an USP approved Type 2 paddle 0067. Additionally, the solid dosage pharmaceutical com apparatus, at a paddle speed of 50 rpm or 100 rpm, and a position disclosed herein, whether whole, flattened, broken, constant temperature of 37+0.5°C. The dissolution test may crushed, or pulverized, forms a viscous mixture or gel when be performed in the presence of 500 mL,900 mL, or 1,000 mL mixed with a small volume of a suitable solvent at a variety of of a suitable dissolution medium. Non-limiting examples of temperatures. The Volume of the Suitable solvent may range suitable dissolution media include water, phosphate buffer from about 3 mL to about 15 mL. In some embodiments, the (pH 6.8), acetate buffer (pH 4.5), and 0.1N HC1. volume may be 5 mL, and in other embodiments, the volume 0063. The pharmaceutical compositions disclosed herein may be 10 mL. Suitable solvents include water, alcohols such provide immediate release of the API. In some embodiments, as ethanol, acids such as acetic acid, fruit juice, and mixtures the pharmaceutical composition may have an average release of any of the foregoing. The temperature of the extraction of about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, may range from about 4° C. to about 100° C. In certain 95%, or 99% of the API within 45 minutes in the dissolution embodiments, the temperature of the extraction may be about US 2016/0000703 A1 Jan. 7, 2016

room temperature (i.e., about 23-25°C.), about 30°C., about the mass of the tablet may be range from about 100 mg to 60° C., or about 90° C. The duration of the extraction may about 1000 mg. In exemplary embodiments, the mass of the range from about 5 minutes to about 3 hours. In some embodi tablet may range from about 300 mg to about 500 mg. The ments, the duration of the extraction may be about 30 minutes Solid dosage unit may be scored by selecting the appropriate or about 60 minutes. The viscosity of the mixture or gel dies and/or punches. prevents the mixture or gel from being drawn through an injection Syringe needle. Consequently, the pharmaceutical (c) Heating the Solid Dosage Unit compositions disclosed herein are resistant to abuse by 0072 The process further comprises heating the solid dos extraction, filtering, and/or injection. age unit from step (b). This heating step dries and cures the Solid dosage unit, wherein the cured solid dosage form may (II) Processes for Preparing Solid Dosage Pharmaceutical have improved properties or characteristics relative to an Compositions uncured solid dosage unit. For example, the heating step may 0068 Another aspect of the disclosure encompasses pro remove water from the Solid dosage form, thereby protecting cesses for preparing Solid dosage forms of the pharmaceutical the effervescent system from premature effervescence. Addi compositions disclosed herein. The processes comprise: (a) tionally, the heating step may plasticize Some of the polymers, forming a mixture comprising at least one non-cellulose thereby leading to increased resistance to crushing/pulveri polysaccharide, at least one hydrophilic gelling polymer, and zation and/or to more rapid release of the API. an effervescent system; (b) forming the mixture into a solid 0073. In general, the heating step occurs at a temperature dosage unit; and (c) heating the Solid dosage unit to form the of less than about 90° C. In various embodiments, the solid Solid dosage form. The solid dosage form optionally may be dosage unit may be heated at a temperature from about 30°C. scored and optionally may be coated with a water-soluble film to about 35° C., from abut 35° C. to about 40°C., from about coating. 40° C. to about 45° C., from about 45° C. to about 50° C. from about 50° C. to about 55° C., from about 55° C. to about 60° (a) Forming a Mixture C., from about 60° C. to bout 65° C., from about 65° C. to 0069. The first step of the process comprises forming a about 70° C., from about 70° C. to about 75°C., from abut 75° mixture comprising the components of the pharmaceutical C. to about 80°C., from about 80°C. to about 85°C., or from composition, which are detailed above in section (I)(a). In about 85°C. to about 903. In specific embodiments, the general, the mixture comprises at least one API, at least one heating temperature may range from about 50° C. to about non-cellulose polysaccharide, at least one hydrophilic gelling 850 C. polymer, an effervescent system comprising an acid compo 0074 The duration of the heating step can and will vary nent and a base component, and a lubricant. The components depending upon the components of the composition and the may be combined in any order or may be premixed in various heating temperature. The duration of the heating step may combinations before being combined together. For example, range from about 10 minutes to about 20 hours. In some in one embodiment the acid component of the effervescent embodiments, the duration of the heating step may range system may be co-processed with a polyalkylene glycol or from about 10 to about 60 minutes, from about 1 to about 2 poloxamer prior to being mixed with the rest of the compo hours, from about 2 to about 3 hours, from about 3 to about 5 nents. In another embodiment, the API may be combined with hours, from about 5 to about 10 hours, or from about 10 to some of the components before being combined with the rest about 20 hours. In general, the higher the temperature, the of the components. Thus, a variety of ordered mixing shorter the duration of time for heating. schemes are possible. 0075. In specific embodiments, the solid dosage unit may 0070 The mixture comprising the components of the be heated to a temperature from about 65° C. to about 80°C. pharmaceutical composition may beformed by mixing, roller for a period of time ranging from about 1 hour to about 3 mixing, drum mixing, shear mixing, dry blending, chopping, hours. milling, roller milling, granulating, dry granulating (e.g., slugging or roller compacting), wet granulating (e.g., fluid (d) Optionally Coating the Solid Dosage Form bed granulating, high shear granulating), and other mixing 0076. The solid dosage form may be coated with a film techniques known in the art. coating. Suitable film coatings are detailed above in section (I)(a)(viii). The optional coating may be applied to the solid (b) Forming a Solid Dosage Unit dosage unit prior to the heating step, or the optional coating 0071. The process further comprises forming the mixture may be applied to the Solid dosage form after the heating step. from step (a) into a solid dosage unit. Suitable solid dosage DEFINITIONS units are described above in section (I)(b). Means of forming Solid dosage units are well known in the art. See, e.g., 0077. When introducing components of the embodiments Gennaro, A. R., editor. “Remington: The Science & Practice described herein, the articles “a”, “an', “the' and “said are of Pharmacy, 21st ed., 2006, Williams & Williams, and in intended to mean that there are one or more of the elements. the “Physician's Desk Reference', 66" ed., 2014, PDR Staff. The terms “comprising”, “including and “having are In specific embodiments, the Solid dosage unit may be a intended to be inclusive and mean that there may be addi tablet. The tablet may be a compression tablet, a molded tional components other than the listed components. tablet, a compacted tablet, or a pressed tablet. In exemplary 0078 If the components described herein have asymmet embodiments, the tablet may be formed by direct compres ric centers, all chiral, diastereomeric, racemic forms and all sion. The shape of the tablet may vary. Non-limiting tablet geometric isomeric forms of a structure are intended, unless shapes include round, oval, rectangular, and triangular. The the specific stereochemistry or isomeric form is specifically size and mass of the tablet may vary. In various embodiments, indicated. US 2016/0000703 A1 Jan. 7, 2016

0079. As used herein, “abuse deterrent refers to any prop Example 2 erty or feature of a pharmaceutical composition that lessens the potential for abuse of the active ingredient(s) in the com position. Dissolution Analysis of Formulations 1-3 0080. The terms “gum' or “natural gum” refer to water soluble and/or water-swellable polysaccharides derived from 0086 The in vitro release of oxycodone hydrochloride natural sources, or structurally modified derivatives thereof, was determined using an USP approved test. The dissolution which are capable of forming highly viscous gels even at low parameters were: USP Apparatus Type 2 (paddles), 50 rpm, concentrations. and 500 mL water or 0.1 NHCl, at 37°+0.5° C. The amount 0081. The term “hydrophilic gelling polymer refers to a of oxycodone HCl in the dissolution fluid was determined at polymer with affinity for water such that it readily absorbs regular intervals. The dissolution data are presented in Tables water or an aqueous solution and/or Swells when in contact 2 and 3. All three formulations exhibited immediate release of with water or an aqueous solution to form a viscous mixture the active ingredient. or gel. 0082. As used herein, “immediate release' refers to an TABLE 2 average release of at least 70% of the API within 45 minutes using a USP approved in vitro release procedure. Dissolution of Tablets in Water - Formulations 1 and 2 0083. Having described the invention in detail, it will be 20 Oxycodone HCI Dissolved apparent that modifications and variations are possible with out departing from the scope of the invention defined in the Formulation 1 Formulation 2 appended claims. Time Uncured Uncured (minutes) Tablet Cured Tablet Tablet Cured Tablet EXAMPLES 5 67.0 65.6 73.7 63.6 0084. The following examples are included to illustrate, 10 89.0 88.7 86.6 89.1 but not to limit the claimed pharmaceutical compositions and 15 90.2 90.6 89.0 91.2 2O 90.6 90.7 89.5 91.4 processes for making. 30 90.4 91.0 89.5 90.9 Example 1 45 90.0 90.3 90.3 92.0 Preparation of Formulations 1-3 TABLE 3 0085. A 50g batch of each formulation presented below in Table 1 was prepared by combining all the components Dissolution of Cured Tablets in 0.1N except magnesium Stearate in a plastic bag and manually HC - Formulations 2 and 3 blending the mixture for 5 minutes. The magnesium Stearate Time % Oxycodone HCl Dissolved was then added and the mixture was blended for an additional 2-3 minutes. The blends were then compressed into oval (minutes) Formulation 2 Formulation 3 tablets using a single-station Natoli tablet press at a compres 5 70.6 49.9 10 95.3 81.6 sion force of about 21 kN. The tablets were placed in an 15 97.0 95.4 aluminum pan and cured in a laboratory oven by heating at 2O 96.9 97.4 80° C. for 3 hours. TABLE 1. Compositions of Formulations 1, 2, and 3 Formulation 1 Formulation 2 Formulation 3 Ingredient mg tablet % w/w mg tablet % wiw mg tablet % wiw Oxycodone HCI 30.84 6.56 30.84 6.17 3O84 5.51 L-(+)-Tartaric acid, extra 122.OO 25.96 122.00 24.40 122.OO 21.79 fine PEG 3350 7.05 1.5 7.05 1.41 7.05 1.26 Effer-Soda (R) 12 104.OO 22.13 104.00 20.80 104.00 18.57 Polyox N10 LEO (10OK) 103.40 22.00 103.40 20.68 10340 18.46 Butylated hydroxytoluene O.O6 O.O13 O.O6 O.O12 OO6 O.O11 Citric acid, anhydrous 4.70 1.00 4.70 O.94 470 O.84 Polyox WSR301 NF 4.25 O.90 4.25 O.85 4.25 O.76 LEO (4 million) Glucomannan 90.60 19.28 12O60 24.12 12O60 21.54 Klucel HF (HPC) (1.15 O O O O 60.00 10.71 million) Magnesium stearate 3.10 O.66 3.10 O.62 3.10 0.55

Total 47O.OO 100.00 SOO.OO 100.00 S6O.OO 100.00 US 2016/0000703 A1 Jan. 7, 2016 10

TABLE 3-continued TABLE 5

Dissolution of Cured Tablets in 0.1N Extraction Data from Cut Tablets - Formulations 2 and 3 HC - Formulations 2 and 3 Amount of Oxycodone Time % Oxycodone HCl Dissolved Volume Extracted

(minutes) Formulation 2 Formulation 3 Extraction Recov- % Sam- Extraction Extraction Volume ered (in 30 96.6 97.5 ple Solvent Temperature (mL) (mL) mg theory) 45 98.2 97.5 F2 Water Room Temp 5 1.1 6.4 21.2 F3 Water Room Temp 5 O6 4.0 13.4 F2 Water Room Temp 10 3.3 8.7 29.1 F3 Water Room Temp 10 1.4 4.1 13.7 Example 3 F2 95% EtOH Room Temp 5 3.1 S4 17.9 F3 95% EtOH Room Temp 5 3.1 3.0 1O.O F2 95% EtOH Room Temp 10 7.1 7.1 23.8 Abuse Deterrence Tests—Crushing F3 95% EtOH Room Temp 10 7.1 4.0 13.5 F2 Water 90° C. 5 O6 2.4 7.9 F3 Water 90° C. 5 O.9 3.1 10.3 0087 Cured tablets from Formulations 1-3 were milled F2 Water 90° C. 10 4.4 11.8 39.3 under high-shear conditions with a Cuisinart DCG-20N cof F3 Water 90° C. 10 3.6 9.7 32.3 fee grinder. The grinder was paused for 30 seconds after each F2 95% EtOH 60° C. 5 3.1 9.O 29.9 F3 95% EtOH 60° C. 5 2.9 7.6 25.4 30 seconds of milling for a total milling time of 3 minutes F2 95% EtOH 60° C. 10 7.2 9.0 30.2 (i.e., six pulses of 30 seconds). The milled products were F3 95% EtOH 60° C. 10 6.8 64 21.3 characterized by particle size analysis. Table 4 presents the particle size data from the milling experiments, with the par ticle size reported as greater than 500 um, from 250-500 um, 0090. In another test, cured tablets from Formulations 1,2, and less than 250 um. In general, particles greater than 250 and 3 were milled into particles as described above and the um are considered difficult to Snort, and hence, formulations particles were extracted (no stirring) with 10 mL of water or resulting in a large fraction of particles greater than 250 um 95% ethanol for 30 minutes at room temperature, 60°C., or are assumed to have better deterrence against this route of 90° C. At the end of the extraction period, the supernatant abuse. liquid was filtered through a cotton plug into a syringe. The amount of oxycodone HCl in the extract was determined by TABLE 4 HPLC and expressed as a fraction of the total amount of Particle Size Distribution of Cured Tablets - Formulations 1-3 oxycodone HCl in the tablets. The results are shown in Table 6. Weight fraction TABLE 6 >500 m 250-500 m <250 m Formulation 1 4.1 25.8 62.9 Extraction Data from Pulverized Tablets - Formulations 1-3 Formulation 2 3.3 26.7 66.6 Formulation 3 2.4 23.1 72.7 Amount of Oxycodone Volume Extracted

Extraction Extraction Recovered % Sample Solvent Temperature (mL) ng (in theory) Example 4 F1 Water Room Temp 7.8 11.21 37.4 F2 Water Room Temp 6.O 7.99 26.6 F3 Water Room Temp 6.5 6.18 20.6 Abuse Deterrence Tests—Extraction with Solvents F1 95% EtOH Room Temp 7.0 4.39 14.6 F2 95% EtOH Room Temp 6.9 5.76 19.2 0088 Tablets from Formulations 1-3 were tested to deter F3 95% EtOH Room Temp 6.3 740 24.7 F1 Water 90° C. 8.2 1740 58.0 mine how much oxycodone could be extracted with various F2 Water 90° C. 8.2 12.24 40.8 Solvents and at various temperatures. The less active ingredi F3 Water 90° C. 8.1 9.SO 31.7 ent that is extracted, the better deterrence provided by the F1 95% EtOH 60° C. 7.0 8.OS 26.8 F2 95% EtOH 60° C. 7.0 10.02 33.4 formulation against abuse IV administration. F3 95% EtOH 60° C. 4.5 9. OS 30.2 0089. In one test, cured tablets from Formulations 2 and 3 were cut into 8 pieces with a razor blade and the resultant pieces were extracted (no stirring) with 5 mL or 10 mL of water or 95% ethanol for 30 minutes at room temperature, 60° Example 5 C., or 90° C. At the end of the extraction period, the superna tant liquid was filtered through a cotton plug into a syringe. Preparation of Formulations 4 and 5 The amount of oxycodone HCl in the extract was determined by HPLC and expressed as a fraction of the total amount of 0091 Formulations were prepared, tableted, and cured oxycodone HCl in the tablets. The results are shown in Table essentially as described in Example 1 using the ingredients 5. listed in Table 7. US 2016/0000703 A1 Jan. 7, 2016

TABLE 7 acceptable salt thereof, at least one non-cellulose polysaccha ride, at least one hydrophilic gelling polymer, and an effer Compositions of Formulations 4 and 5 Vescent system. 2. The pharmaceutical composition of claim 1, wherein at Formulation 4 Formulation 5 least about 70% of the API is released within about 45 min Ingredient mg tablet % w/w mg tablet % wiw utes when dissolution is measured using an USP-approved in vitro release procedure. Oxycodone HCI 30.84 6.43 30.84 6.17 3. The pharmaceutical composition of claim 1, wherein a L-(+)-Tartaric acid, extra fine 122.OO 2S.42 122.OO 24-40 PEG 3350 7.05 1.47 7.05 1.41 plurality of particles having an average diameter greater than Effer-Soda (R) 12 104.OO 21.67 104.OO 20.80 about 250 microns is formed when the composition is Polyox N10 LEO (10OK) 103.40 21.54 103.40 20.68 crushed, ground, or pulverized. Butylated hydroxytoluene O.O6 O.O1 O.O6 O.O1 4. The pharmaceutical composition of claim 1, wherein the Citric acid, anhydrous 4.70 O.98 4.70 O.94 non-cellulose polysaccharide is a natural gum, hemicellulose, Polyox WSR301 NF LEO 4.25 O.89 4.25 O.85 (4M) pectin, chitin, starch, or a combination thereof, and the non Glucomannan 40.OO 8.33 6O.OO 12.00 cellulose polysaccharide is present in an amount from about Sodium 2O.OO 4.17 2O.OO 4.OO 2% to about 60% by weight of the pharmaceutical composi carboxymethylcellulose (30K) tion. Methocel K10OM CR (250K) 3O.OO 6.25 3O.OO 6.OO 5. The pharmaceutical composition of claim 1, wherein the Xanthan gum (Vanzan NF) 10.60 2.21 10.60 2.12 hydrophilic gelling polymer is a cellulose ether, a polyalky Magnesium stearate 3.10 O.65 3.10 O.62 lene oxide, a polyacrylic acid, or a combination thereof, and the hydrophilic gelling polymer is present in an amount from Total 48O.OO 10O.OO SOO.OO 100.00 about 5% to about 80% by weight of the pharmaceutical composition. 6. The pharmaceutical composition of claim 1, wherein the Example 6 effervescent system comprises a) an acid component chosen from an organic acid, an inorganic acid, or a combination Abuse Deterrence Tests—Extraction with Solvents thereof, and b) a base component chosen from an alkali metal bicarbonate, an alkaline earth metal bicarbonate, an alkali 0092. Cured tablets from Formulations 4 and 5 were cut metal carbonate, an organic carbonate, or a combination into 8 pieces with a razor blade and the resultant pieces were thereof, and the effervescent system is present in an amount extracted (no stirring) with 5 mL or 10 mL of water or 95% from about 20% to about 90% by weight of the pharmaceu ethanol for 30 minutes at room temperature, 60°C., or 90° C. tical composition. At the end of the extraction period, the Supernatant liquid was 7. The pharmaceutical composition of claim 1, wherein the filtered through a cotton plug into a Syringe. The amount of API is an opioid or a combination of an opioid and a non oxycodone HCl in the extract was determined by HPLC and opioid analgesic, and the opioid is oxycodone, oxymorphone, expressed as a fraction of the total amount of oxycodone HC1 hydrocodone, hydromorphone, codeine, or morphine. in the tablets. The results are shown in Table 8. 8. The pharmaceutical composition of claim 1, wherein the non-cellulose polysaccharide is glucomannan, Xanthan gum, TABLE 8 or a combination thereof; the hydrophilic gelling polymer is polyethylene oxide, hydroxypropylmethylcellulose, hydrox Extraction Data from Cut Tablets - Formulations 4 and 5 ypropylcellulose, sodium carboxymethylcellulose, or a com Amount of bination thereof, and the effervescent system comprises a) an Oxycodone acid component comprising an organic acid and b) a base Volume Extracted component comprising an alkali metal bicarbonate. 9. The pharmaceutical composition of claim 8, wherein the Extraction Recov- % Sam- Extraction Extraction Volume ered (in non-cellulose polysaccharide is present in an amount from ple Solvent Temperature (mL) (mL) mg theory) about 5% to about 40% by weight of the pharmaceutical composition; the hydrophilic gelling polymer is present in an F4 Water Room Temp 5 O.9 3.1 10.3 F5 Water Room Temp 5 O.9 2.4 8.1 amount from about 10% to about 50% by weight of the F4 Water Room Temp O 2.9 6.4 21.2 pharmaceutical composition; and the effervescent system is F5 Water Room Temp O 3.4 5.7 18.9 present in an amount from about 30% to about 60% by weight F4 95% EtOH Room Temp 5 3.1 5.3 17.8 of the pharmaceutical composition. F5 95% EtOH Room Temp 5 3.1 4.7 15.8 10. The pharmaceutical composition of claim 9, wherein F4 95% EtOH Room Temp O 7.2 6.4 21.2 F5 95% EtOH Room Temp O 7.1 5.3 17.7 the API is oxycodone, oxymorphone, hydrocodone, hydro F4 Water 90° C. 5 1.5 S.6 18.8 morphone, codeine, or morphine. F5 Water 90° C. 5 1.5 3.3 11.1 11. The pharmaceutical composition of claim 1, wherein F4 Water 90° C. O 5.7 10.6 35.4 the pharmaceutical composition is a Solid dosage form. F5 Water 90° C. O 4.9 10.3 34.4 F4 95% EtOH 60° C. 5 3.2 9.0 30.1 12. The pharmaceutical composition of claim 11, wherein F5 95% EtOH 60° C. 5 3.2 8.2 27.4 the Solid dosage form is prepared by a process comprising: F4 95% EtOH 60° C. O 7.2 94 31.4 a) forming a mixture comprising the API or pharmaceuti F5 95% EtOH 60° C. O 7.0 9.8 32.8 cally acceptable salt thereof, the non-cellulose polysac charide, the hydrophilic gelling polymer, and the effer Vescent system; What is claimed is: b) forming the mixture into a solid dosage unit; and 1. A pharmaceutical composition comprising at least one c) heating the Solid dosage unit to yield the Solid dosage active pharmaceutical ingredient (API) or a pharmaceutically form. US 2016/0000703 A1 Jan. 7, 2016

13. An abuse deterrent solid dosage form comprising at thereof, and the effervescent system comprises an organic least one active pharmaceutical ingredient (API) Susceptible acid and an alkali metal bicarbonate. to abuse or a pharmaceutically acceptable salt thereof, at least 17. The abuse deterrent solid dosage form of claim 16, one natural gum, at least one hydrophilic gelling polymer, and wherein the natural gum is present in an amount from about an effervescent system. 5% to about 40% by weight of the solid dosage form; the hydrophilic gelling polymer is present in an amount from 14. The abuse deterrent solid dosage form of claim 13, about 10% to about 50% by weight of the solid dosage form: wherein the Solid dosage from is resistant to crushing, grind and the effervescent system is present in an amount from ing, cutting, or pulverizing to form a fine powder and is about 30% to about 60% by weight of the solid dosage form. resistant to extraction with an aqueous solvent. 18. The abuse deterrent solid dosage form of claim 17, wherein the API is an opioid or a combination of an opioid 15. The abuse deterrent solid dosage form of claim 13, and a non-opioid analgesic, and the opioid is oxycodone, wherein at least about 70% of the API is released within about oxymorphone, hydrocodone, hydromorphone, codeine, or 45 minutes when dissolution is measured using an USP morphine. approved in vitro release procedure. 19. The abuse deterrent solid dosage of claim 18, wherein 16. The abuse deterrent solid dosage form of claim 13, the API is oxycodone. wherein the gum is glucomannan, Xanthan gum, or a combi 20. The abuse deterrent solid dosage form of claim 13, nation thereof; the hydrophilic gelling polymer is polyethyl wherein the solid dosage form is cured by heating at a tem ene oxide, hydroxypropylmethylcellulose, hydroxypropyl perature of less than about 90° C. cellulose, sodium carboxymethylcellulose, or a combination k k k k k